Fungicides for the control of take-all disease of plants

ABSTRACT

A method of controlling Take-all disease of plants by applying, preferably to the seed prior to planting, a fungicide of the formula ##STR1## wherein Z 1  and Z 2  are C and are part of an aromatic ring that is furan; 
     A is selected from --C(X)-amine, --C(O)--SR 3 , --NH--C(X)R 4 , and --C(═NR 3 )--XR 7  ; 
     B is --W m  --Q(R 2 ) 3  or selected from o-tolyl, 1-naphthyl, 2-naphthyl, and 9-phenanthryl, each optionally substituted with halogen or R 4  ; 
     Q is C, Si, Ge, or Sn; 
     W is --C(R 3 ) p  H.sub.(2-p) --; or when Q is C, W is selected from --C(R 3 ) p  H.sub.(2-p) --, --N(R 3 ) m  H.sub.(1-m) --, --S(O) p  --, and --O--; 
     X is O or S; 
     n is 2; 
     m is 0 or 1; 
     p is 0, 1, or 2; 
     R, R 2 , R 3 , R 4  and R 7  are herein defined; 
     or an agronomic salt thereof.

This application is a divisional of U.S. Ser. No. 08/365,391 filed Dec.28, 1994, now U.S. Pat. No. 5,693,667, which is a divisional of U.S.Ser. No. 08/238,182 filed May 4, 1994, abandoned, which is acontinuation of U.S. Ser. No. 07/951,997 filed Oct. 2, 1992, abandoned,which is a continuation-in-part of Ser. No. 07/780,683 filed Oct. 18,1991, abandoned.

FIELD OF THE INVENTION

This invention relates to a method for the control of Take-All diseasein plants, particularly cereals, by the use of certain substituted arylcompounds, some of which are novel, and fungicidal compositions forcarrying out the method.

BACKGROUND OF THE INVENTION

Take-all disease is a serious problem in the production of cereals,particularly wheat and barley. It is caused by the soil-borne fungusGaeumannomyces graminis (Gg). The fungus infects the roots of the plant,and grows throughout the root tissue, causing a black rot. The growth ofthe fungus in the roots and lower stem prevents the plant from obtainingsufficient water and/or nutrients from the soil, and is manifested aspoor plant vigor and, in severe instances of disease, by the formationof "whiteheads," which are barren or contain few, shriveled grains.Yield losses result. Gaeumannomyces species also infect other cerealcrops, for example, rice and oats; and turf.

Currently the primary means of avoiding crop loss due to infestation ofthe soil by Gg has been to rotate the crop grown to one which isresistant to Gg. However, in areas where the primary crops are cereals,rotation is not a desirable practice, and an effective control agent isgreatly desired.

It is an object of this invention to provide an effective method forcontrol of Take-all disease in plants. It is a further object of thisinvention to provide compounds that control the growth of Gg in the soilso as to reduce crop loss. It is still a further object of thisinvention to provide fungicidal compositions that may be used forcontrol of Take-all disease.

SUMMARY OF THE INVENTION

The present invention provides a method of controlling disease caused byGaeumannomyces species in plants comprising applying to the plant locus,that is, the plant itself, its seed, or the soil, a fungicidallyeffective amount of a fungicide of the formula ##STR2## wherein Z₁ andZ₂ are C or N and are part of an aromatic ring selected from benzene,pyridine, thiophene, furan, pyrrole, pyrazole, thiazole, andisothiazole;

A is selected from --C(X)-amine, --C(O)--SR₃, --NH--C(X)R₄, and--C(═NR₃)--XR₇ ;

B is --W_(m) --Q(R₂)₃ or selected from o-tolyl, 1-naphthyl, 2-naphthyl,and 9-phenanthryl, each optionally substituted with halogen or R₄ ;

Q is C, Si, Ge, or Sn;

W is --C(R₃)_(p) H.sub.(2-p) --; or when Q is C, W is selected from--C(R₃)_(p) H.sub.(2-p) --, --N(R₃)_(m) H.sub.(1-m) --, --S(O)_(p) --,and --O--;

X is O or S;

n is 0, 1, 2, or 3;

m is 0 or 1;

p is 0, 1, or 2;

each R is independently selected from

a) halo, formyl, cyano, amino, nitro, thiocyanato, isothiocyanato,trimethylsilyl, and hydroxy;

b) C1-C4 alkyl, alkenyl, alkynyl, C3-C6 cycloalkyl, and cycloalkenyl,each optionally substituted with halo, hydroxy, thio, amino, nitro,cyano, formyl, phenyl, C1-C4 alkoxy, alkylcarbonyl, alkylthio,alkylamino, dialkylamino, alkoxycarbonyl, (alkylthio)carbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfinyl, oralkylsulfonyl;

c) phenyl, furyl, thienyl, pyrrolyl, each optionally substituted withhalo, formyl, cyano, amino, nitro, C1-C4 alkyl, alkenyl, alkynyl,alkoxy, alkylthio, alkylamino, dialkylamino, haloalkyl, and haloalkenyl;

d) C1-C4 alkoxy, alkenoxy, alkynoxy, C3-C6 cycloalkyloxy,cycloalkenyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino,dialkylamino, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl,(alkylthio)carbonyl, phenylcarbonylamino, phenylamino, each optionallysubstituted with halo;

wherein two R groups may be combined to form a fused ring;

each R₂ is independently selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl and phenyl, each optionally substituted with R₄or halogen; and wherein, when Q is C, R₂ may also be selected from halo,alkoxy, alkylthio, alkylamino, and dialkylamino;

wherein two R₂ groups may be combined to form a cyclo group with Q;

R₃ is C1-C4 alkyl;

R₄ is C1-C4 alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, ordialkylamino;

R₇ is C1-C4 alkyl, haloalkyl, or phenyl, optionally substituted withhalo, nitro, or R₄ ;

or an agronomic salt thereof.

The term "amine" in --C(X)-amine means an unsubstituted,monosubstituted, or disubstituted amino radical, includingnitrogen-bearing heterocycles. Examples of substituents for the aminoradical include, but are not limited to, hydroxy; alkyl, alkenyl, andalkynyl, which may be straight or branched chain or cyclic; alkoxyalkyl;haloalkyl; hydroxyalkyl; alkylthio; alkylthioalkyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonyl; alkylaminocarbonyl; cyanoalkyl; mono- ordialkylamino; phenyl, phenylalkyl or phenylalkenyl, each optionallysubstituted with one or more C1-C6 alkyl, alkoxy, haloalkyl, C3-C6cycloalkyl, halo, or nitro groups; C1-C4 alkyl or alkenyl groupssubstituted with heterocycles, optionally substituted with one or moreC1-C4 alkyl, alkoxy, haloalkyl, halo, or nitro groups. Examples of suchnitrogen-bearing heterocycles, which are bonded at a nitrogen to--C(X)--, include, but are not limited to, morpholine, piperazine,piperidine, pyrrole, pyrrolidine, imidazole, and triazoles, each ofwhich may be optionally substituted with one or more C1-C6 alkyl groups.

Specific examples of the amino radicals useful in the present inventioninclude, but are not limited to, ethylamino, methylamino, propylamino,2-methylethylamino, 1-propenylamino, 2-propenylamino,2-methyl-2-propenylamino, 2-propynylamino, butylamino,1,1-dimethyl-2-propynylamino, diethylamino, dimethylamino,N-(methyl)ethylamino, N-(methyl)-1,1-(dimethyl)ethylamino,dipropylamino, octylamino, N-(ethyl)-1-methylethylamino,2-hydroxyethylamino, 1-methylpropylamino, chloromethylamino,2-chloroethylamino, 2-bromoethylamino, 3-chloropropylamino,2,2,2-trifluoroethylamino, cyanomethyl, methylthiomethylamino,(methylsulfonyl)oxyethylamino, 2-ethoxyethylamino, 2-methoxyethylamino,N-(ethyl)-2-ethoxyethylamino, 1-methoxy-2,2-dimethylpropylamino,cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino,methoxymethylamino, N-(methoxymethyl)ethylamino,N-(1-methylethyl)propylamino, 1-methylheptylamino,N-(ethyl)-1-methylheptylamino, 6,6-dimethyl-2-hepten-4-ynylamino,1,1-dimethyl-2-propynylamino. Further examples include benzylamino,ethylbenzylamino, 3-methoxybenzylamino, 3-(trifluoromethyl)benzylamino,N-methyl-3-(trifluoromethyl)benzylamino, 3,4,5-trimethoxybenzylamino,1,3-benzodioxol-5-ylmethylamino, phenylamino,3-(1-methylethyl)phenylamino, ethoxyphenylamino, cyclopentylphenylamino,methoxyphenylamino, nitrophenylamino, 1-phenylethylamino,N-(methyl)-3-phenyl-2-propenylamino, benzotriazolylphenylmethyl,2-pyridinylmethylamino, N-(ethyl)-2-pyridinylmethylamino,2-thienylmethylamino, and furylmethylamino. Further examples of aminoradicals include methylhydrazino, dimethylhydrazino, N-ethylanilino, and2-methylanilino. The amine may also be substituted with diethylN-ethylphosphoramidic acid, t-butoxycarbonyl, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, etc. Of these examples of the aminoradical, ethylamino is preferred.

Examples of B include, but are not limited to, trimethylsilyl,ethyldimethylsilyl, diethylmethylsilyl, triethylsilyl,dimethylpropylsilyl, dipropylmethylsilyl, dimethyl-1-(methyl)ethylsilyl,tripropylsilyl, butyldimethylsilyl, pentyldimethylsilyl,hexyldimethylsilyl, cyclopropyldimethylsilyl, cyclobutyldimethylsilyl,cyclopentyldimethylsilyl, cyclohexyldimethylsilyl, dimethylethenylsilyl,dimethylpropenylsilyl, chloromethyldimethylsilyl,2-chloroethyldimethylsilyl, bromomethyldimethylsilyl,bicycloheptyldimethylsilyl, dimethylphenylsilyl,dimethyl-2-(methyl)phenylsilyl, dimethyl-2-fluorophenylsilyl, and othersuch silyl groups of the formula Si(R₂)₃ ; any such silyl groupconnected to the Z₁ --Z₂ ring by a methylene group; and any of thesegroups wherein germanium or tin is substituted for silicon. Of theseexamples of B, trimethylsilyl is preferred.

Further examples of B include 1,1-dimethylethyl, 1,1-dimethylpropyl,1,1-dimethylbutyl, 1,1-dimethylpentyl, 1-ethyl-1-methylbutyl,2,2-dimethylpropyl, 2,2-dimethylbutyl, 1-methyl-1-ethylpropyl,1,1-diethylpropyl, 1,1,2-trimethylpropyl, 1,1,2-trimethylbutyl,1,1,2,2-tetramethylpropyl, 1,1-dimethyl-2-propenyl,1,1,2-trimethyl-2-propenyl, 1,1-dimethyl-2-butenyl,1,1-dimethyl-2-propynyl, 1,1-dimethyl-2-butynyl,1-cyclopropyl-1-methylethyl, 1-cyclobutyl-1-methylethyl,1-cyclopentyl-1-methylethyl, 1-(1-cyclopentenyl)-1-methylethyl,1-cyclohexyl-1-methylethyl, 1-(1-cyclohexenyl)-1-methylethyl,1-methyl-1-phenylethyl, 1,1-dimethyl-2-chloroethyl,1,1-dimethyl-3-chloropropyl, 1,1-dimethyl-2-methoxyethyl,1,1-dimethyl-2-(methylamino)ethyl, 1,1-dimethyl-2-(dimethylamino)ethyl,1,1-dimethyl-3-chloro-2-propenyl, 1-methyl-1-methoxyethyl,1-methyl-1-(methylthio)ethyl, 1-methyl-1-(methylamino)ethyl,1-methyl-1-(dimethylamino)ethyl, 1-chloro-1-methylethyl,1-bromo-1-methylethyl, and 1-iodo-1-methylethyl. Of these examples of B,1,1-dimethylethyl is preferred.

Further examples of B are 1,1-dimethylethylamino,1,1-dimethylpropylamino, 1,1-dimethylbutylamino,1,1-dimethylpentylamino, 1-ethyl-1-methylbutylamino,2,2-dimethylpropylamino, 2,2-dimethylbutylamino,1-methyl-1-ethylpropylamino, 1,1-diethylpropylamino,1,1,2-trimethylpropylamino, 1,1,2-trimethylbutylamino,1,1,2,2-tetramethylpropylamino, 1,1-dimethyl-2-propenylamino,1,1,2-trimethyl-2-propenylamino, 1,1-dimethyl-2-butenylamino,1,1-dimethyl-2-propynylamino, 1,1-dimethyl-2-butynylamino,1-cyclopropyl-1-methylethylamino, 1-cyclobutyl-1-methylethylamino,1-cyclopentyl-1-methylethylamino,1-(1-cyclopentenyl)-1-methylethylamino, 1-cyclohexyl-1-methylethylamino,1-(1-cyclohexenyl)-1-methylethylamino, 1-methyl-1-phenylethylamino,1,1-dimethyl-2-chloroethylamino, 1,1-dimethyl-3-chloropropylamino,1,1-dimethyl-2-methoxyethylamino,1,1-dimethyl-2-(methylamino)ethylamino,1,1-dimethyl-2-(dimethylamino)ethylamino, and1,1-dimethyl-3-chloro-2-propenylamino. Any of these groups may also havea methyl substitution on the nitrogen, as inN-(methyl)-1,1-dimethylethylamino andN-(methyl)-1,1-dimethylpropylamino. Of these examples of B,1,1-dimethylethylamino and N-(methyl)-1,1-dimethylethylamino arepreferred.

Further examples of B include 1,1-dimethylethoxy, 1,1-dimethylpropoxy,1,1-dimethylbutoxy, 1,1-dimethylpentoxy, 1-ethyl-1-methylbutoxy,2,2-dimethylpropoxy, 2,2-dimethylbutoxy, 1-methyl-1-ethylpropoxy,1,1-diethylpropoxy, 1,1,2-trimethylpropoxy, 1,1,2-trimethylbutoxy,1,1,2,2-tetramethylpropoxy, 1,1-dimethyl-2-propenoxy,1,1,2-trimethyl-2-propenoxy, 1,1-dimethyl-2-butenoxy,1,1-dimethyl-2-propynyloxy, 1,1-dimethyl-2-butynyloxy,1-cyclopropyl-1-methylethoxy, 1-cyclobutyl-1-methylethoxy,1-cyclopentyl-1-methylethoxy, 1-(1-cyclopentenyl)-1-methylethoxy,1-cyclohexyl-1-methylethoxy, 1-(1-cyclohexenyl)-1-methylethoxy,1-methyl-1-phenylethoxy, 1,1-dimethyl-2-chloroethoxy,1,1-dimethyl-3-chloropropoxy, 1,1-dimethyl-2-methoxyethoxy,1,1-dimethyl-2-(methylamino)ethoxy,1,1-dimethyl-2-(dimethylamino)ethoxy, 1,1-dimethyl-3-chloro-2-propenoxy.Of these examples of B, 1,1-dimethylethoxy is preferred.

Further examples of B include 1-methylcyclopropyl, 1-methylcyclobutyl,1-methylcyclopentyl, 1-methylcyclohexyl, 1-methylcyclopropylamino,1-methylcyclobutylamino, 1-methylcyclopentylamino,1-methylcyclohexylamino, N-(methyl)-1-methylcyclopropylamino,N-(methyl)-1-methylcyclobutylamino, N-(methyl)-1-methylcyclopentylamino,and N-(methyl)-1-methylcyclohexylamino.

R_(n) may be any substituent(s) which do(es) not unduly reduce theeffectiveness of the compounds to function in the method of diseasecontrol. R_(n) is generally a small group; "n" is preferably 1 forbenzene rings and 2 for furan and thiophene. R is more preferably methylor halogen, and more preferably is located adjacent to A.

The present invention also provides novel compounds of the formula givenabove. However, when Z₁ and Z₂ are part of a benzene ring, the followingare not included as novel compounds: 1) n is not zero when B istrimethylsilyl and A is N,N-diethylaminocarbonyl,N,N-bis(1-methylethyl)aminocarbonyl, N-methylaminothiocarbonyl,N-ethylaminocarbonyl, 1-piperidinylcarbonyl, or N-phenylaminocarbonyl;or when B is orthotolyl and A is N,N-diethylaminocarbonyl,N,N-bis(1-methylethyl)aminocarbonyl, N-methylaminocarbonyl, orO-methylcarbamyl; or when B is 1,1-dimethylethyl and A isN,N-dimethylaminothiocarbonyl or N-phenylaminocarbonyl; or when B istrimethylstannyl and A is N,N-diethylaminocarbonyl orO-(1,1-dimethylethyl)carbamyl; 2) when B is 2-trimethylsilyl and A isN,N-diethylaminocarbonyl, R_(n) is not 3-fluoro-6-formyl,3-fluoro-6-methyl, 3-chloro-6-formyl, 3-fluoro, 3-chloro,3-chloro-6-methyl, 6-trimethylsilyl, or 6-methyl; 3) when A isO-(1,1-dimethylethyl)carbamyl and B is 2-trimethylsilyl, R_(n) is not5-trifluoromethyl; 4) when A is N-phenylaminocarbonyl and B is2,2-dimethylpropyl, R_(n) is not 3-methyl; and 5) R is notisothiocyanato when A is --C(O)-amine and W_(m) is --O--.

When Z₁ and Z₂ are part of a thiophene, furan or pyrrole ring, the novelcompounds of the present invention do not include B equal totrimethylsilyl when A is (diethylamino)carbonyl.

The invention also provides fungicidal compositions useful in saidmethod.

As used herein, the term "alkyl", unless otherwise indicated, means analkyl radical, straight or branched chain, having, unless otherwiseindicated, from 1 to 10 carbon atoms. The terms "alkenyl" and "alkynyl"mean unsaturated radicals having from 2 to 7 carbon atoms. Examples ofsuch alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl,1-methylethenyl, and the like. Examples of such alkynyl groups includeethynyl, 1-propynyl, 2-propynyl, 1,1-dimethyl-2-propynyl, and so forth.Substituent groups may also be both alkenyl and alkynyl, for example,6,6-dimethyl-2-hepten-4-ynyl.

As used herein, the term "alkoxy" means an alkyl group having, unlessotherwise indicated, from 1 to 10 carbon atoms connected via an etherlinkage. Examples of such alkoxy groups include methoxy, ethoxy,propoxy, 1-methylethoxy, and so forth.

As used herein, the term "alkoxyalkyl" means an ether radical having,unless otherwise indicated, from 1 to 10 carbon atoms. Examples of suchalkoxyalkyl groups include methoxymethyl, methoxyethyl, ethoxymethyl,ethoxyethyl, and so forth.

As used herein, the terms "monoalkylamino" and "dialkylamino" each meanan amino group having, respectively, 1 or 2 hydrogens replaced with analkyl group.

As used herein, the term "haloalkyl" means an alkyl radical having oneor more hydrogen atoms replaced by halogens, including radicals havingall hydrogen atoms substituted by halogen. Examples of such haloalkylgroups are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,trichloromethyl, and so forth.

As used herein, the term "halo" means a radical selected from chloro,bromo, fluoro, and iodo.

DETAILED DESCRIPTION OF THE INVENTION

Control of Gg diseases, including Take-All, using a chemical controlagent may be accomplished in several ways. The agent may be applieddirectly to soil infested with Gg, for example, at the time of plantingalong with the seed. Alternatively, it may applied after planting andgermination. Preferably, however, it is applied to the seed in a coatingprior to planting. This technique is commonly used in many crops toprovide fungicides for control of various phytopathological fungi.

Compositions of the present invention are comprised of a fungicidallyeffective amount of one or more of the compounds described above and oneor more adjuvants. The active ingredient may be present in suchcompositions at levels from 0.01 to 95 percent by weight. Otherfungicides may also be included to provide a broader spectrum of fungalcontrol. The choice of fungicides will depend on the crop and thediseases known to be a threat to that crop in the location of interest.

The fungicidal compositions of this invention, including concentrateswhich require dilution prior to application, may contain at least oneactive ingredient and an adjuvant in liquid or solid form. Thecompositions are prepared by admixing the active ingredient with anadjuvant including diluents, extenders, carriers, and conditioningagents to provide compositions in the form of finely-divided particulatesolids, granules, pellets, solutions, dispersions or emulsions. Thus, itis believed that the active ingredient could be used with an adjuvantsuch as a finely-divided solid, a liquid of organic origin, water, awetting agent, a dispersing agent, an emulsifying agent or any suitablecombination of these.

Suitable wetting agents are believed to include alkyl benzene and alkylnaphthalene sulfonates, sulfated fatty alcohols, amines or acid amides,long chain acid esters of sodium isothionate, esters of sodiumsulfosuccinate, sulfated or sulfonated fatty acid esters, petroleumsulfonates, sulfonated vegetable oils, ditertiary acetylenic glycols,polyoxyethylene derivatives of alkylphenols (particularly isooctylphenoland nonylphenol) and polyoxyethylene derivatives of the mono-higherfatty acid esters of hexitol anhydrides (e.g., sorbitan). Preferreddispersants are methyl, cellulose, polyvinyl alcohol, sodium ligninsulfonates, polymeric alkyl naphthalene sulfonates, sodium naphthalenesulfonate, and polymethylene bisnaphthalene sulfonate. Stabilizers mayalso be used to produce stable emulsions, such as magnesium aluminumsilicate and xanthan gum.

Other formulations include dust concentrates comprising from 0.1 to 60%by weight of the active ingredient on a suitable extender, optionallyincluding other adjuvants to improve handling properties, e.g.,graphite. These dusts may be diluted for application at concentrationswithin the range of from about 0.1-10% by weight.

Concentrates may also be aqueous emulsions, prepared by stirring anonaqueous solution of a water-insoluble active ingredient and anemulsification agent with water until uniform and then homogenizing togive stable emulsion of very finely-divided particles. Or they may beaqueous suspensions, prepared by milling a mixture of a water-insolubleactive ingredient and wetting agents to give a suspension, characterizedby its extremely small particle size, so that when diluted, coverage isvery uniform. Suitable concentrations of these formulations contain fromabout 0.1-60% preferably 5-50% by weight of active ingredient.

Concentrates may be solutions of active ingredient in suitable solventstogether with a surface active agent. Suitable solvents for the activeingredients of this invention for use in seed treatment includepropylene glycol, furfuryl alcohol, other alcohols or glycols, and othersolvents which do not substantially interfere with seed germination. Ifthe active ingredient is to be applied to the soil, then solvents suchas N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone,hydrocarbons, and water-immiscible ethers, esters, or ketones.

The concentrate compositions herein generally contain from about 1.0 to95 parts (preferably 5-60 parts) active ingredient, about 0.25 to 50parts (preferably 1-25 parts) surface active agent and where requiredabout 4 to 94 parts solvent, all parts being by weight based on thetotal weight of the concentrate.

For application to the soil at the time of planting, a granularformulation may be used. Granules are physically stable particulatecompositions comprising at least one active ingredient adhered to ordistributed through a basic matrix of an inert, finely-dividedparticulate extender. In order to aid leaching of the active ingredientfrom the particulate, a surface active agent such as those listedhereinbefore, or for example, propylene glycol, can be present in thecomposition. Natural clays, pyrophyllites, illite, and vermiculite areexamples of operable classes of particulate mineral extenders. Thepreferred extenders are the porous, absorptive, preformed particles suchas preformed and screened particulate attapulgite or heat expanded,particulate vermiculite and the finely-divided clays such as kaolinclays, hydrated attapulgite or bentonitic clays. These extenders aresprayed or blended with the active ingredient to form the fungicidalgranules.

The granular compositions of this invention may contain from about 0.1to about 30 parts by weight of active ingredient per 100 parts by weightof clay and 0 to about 5 parts by weight of surface active agent per 100parts by weight of particulate clay.

The method of the present invention may be carried out by mixing thecomposition comprising the active ingredient into the seed prior toplanting at rates from 0.01 to 50 g per kg of seed, preferably from 0.1to 5 g per kg, and more preferably from 0.2 to 2 g per kg. Ifapplication to the soil is desired, the compounds may be applied atrates from 10 to 1000 g per hectare, preferably from 50 to 500 g perhectare. The higher application rates will be needed for situations oflight soils or greater rainfall or both.

The compounds useful in the present invention may be prepared by methodsknown to those of ordinary skill in the art. The following examplesillustrate some of these methods and are illustrative only; they are notmeant to be limiting in any way.

Unless otherwise indicated, percentages are given as weight/weight.Melting points and boiling points are reported uncorrected. Thin layerchromatography was carried out with varying concentrations of ethylacetate/hexanes elutions. Tetrahydrofuran and ether solvents weredistilled from sodium metal/benzophenone immediately prior to use.N,N,N',N'-(Tetramethyl)ethylenediamine was distilled from calciumhydride prior to use. All other reagents were purchased from Aldrich orLancaster and used without purification. A measured physical property isreported for each example or the elemental analysis is given at the endof the examples.

The following abbreviations have the meanings shown:

    ______________________________________                                        n-BuLi        n-Butyl lithium                                                   s-BuLi           sec-Butyl lithium                                            t-BuLi           tert-Butyl lithium                                           DAST             Diethylaminosulfur trifluoride                               DEAD             Diethyl azodicarboxylate                                     DMF              Dimethylformamide                                            DMSO             Dimethylsulfoxide                                            TMSCl            Trimethylsilyl chloride                                      THF              Tetrahydrofuran                                              TMEDA            N,N,N',N'-(tetramethyl)ethylenediamine                       eq               equivalent(s)                                                aq               aqueous                                                      sat              saturated                                                    min              minutes                                                      h                hours                                                        MeI              Methyl iodide                                                Lawesson's Reagent   [2,4-bis(4-methoxypheny1)-1,3-                                             dithia-2, 4-diphosphetane-2,4-                                                disulfide]                                                  TLC              Thin Layer Chromatography                                    HPLC             High Pressure Liquid Chromatography                          RC              Radial Chromatography                                         GLC             Gas-liquid Chromatography                                     RT              room temperature                                              m.p.            melting point                                               ______________________________________                                    

General Methods

The phrase "worked up in the usual manner" refers to treatment of thereaction mixture with 10% aq citric acid, extraction with diethyl ether,washing of the combined organic extracts with sat brine solution, dryingof the organic extract over MgSO₄, and evaporation to dryness in vacuoto afford the crude product. The phrase "appropriate" means a compoundhaving the substituents desired for the final product of the reaction.

Method A.

Ortho-introduction of Electrophiles into N,N-dialkylbenzamides.

1.3M s-BuLi in cyclohexane (1.1 to 1.2 molar eq) was added dropwise to adry-ice/acetone or an ether/liquid nitrogen cooled 1.0M solution ofTMEDA (1.0 to 1.2 molar eq) in THF, followed by the dropwise addition ofthe appropriate N,N-dialkylbenzamide (1.0 eq) in THF. The resultingreaction mixture was stirred for 30-60 min at -78° C. to ensure completearyl anion formation, then was cooled to ≦-90° C. with an ether/liquidnitrogen bath and quenched by the careful addition of the appropriateelectrophile. The reaction was allowed to warm slowly to 0° C. then wasworked up in the usual manner. If needed, the crude product was purifiedby chromatography, recrystallization or distillation.

Method B.

Ortho-introduction of Electrophiles into N,N-dialkylbenzamides viaInverse Addition.

1.3M s-BuLi in cyclohexane (1.2 eq) was added dropwise to anether/liquid nitrogen cooled 1.0M solution of TMEDA (1.2 eq) in THF,followed by the dropwise addition of the appropriateN,N-dialkylbenzamide (1.0 eq) in THF. The internal reaction temperaturewas maintained between -80 and -95° C. during both additions. Afteraddition, the cooling bath was replaced with dry-ice/acetone, and theresulting reaction was stirred at -78° C. for 1 h. This solution wasthen cannulaed into a solution of an excess of the appropriateelectrophile in THF at a rate which maintained the internal reactiontemperature below -80° C. with an ether/liquid nitrogen bath. Theresulting reaction mixture was slowly allowed to 0° C. then purified inthe manner described below for each compound.

Method C.

Ortho-introduction of Electrophiles into N-alkylbenzamides.

1.3M s-BuLi in cyclohexane (2.1 to 2.2 eq) was added dropwise to adry-ice/acetone or an ether/liquid nitrogen cooled 1.0M solution ofTMEDA (1.0 to 1.2 eq) in THF, followed by the dropwise addition of theappropriate N-alkylbenzamide (1.0 eq) in THF. The resulting reactionmixture was stirred for 30-60 min at -78° C. to ensure complete arylanion formation, then was cooled to ≦-90° C. with an ether/liquidnitrogen bath and quenched by the careful addition of the appropriateelectrophile. The reaction was allowed to warm slowly to -30° C. thenwas worked up in the usual manner. If needed, the crude product waspurified by chromatography, recrystallization or distillation.

METHOD D.

Boronate Coupling Procedure

The compound of Example f (5.0 g, 27.2 mmol), TMEDA (6.6 g, 57.1 mmol),and THF (100 Ml) were stirred at -78° C. under nitrogen, and 1.3M s-BuLiin cyclohexane (44 mL, 57.1 mmol) was added dropwise. The mixture wasstirred for 15 min and trimethylborate (3.1 g, 29.9 mmol) was added allat once. The mixture was then stirred at -78° C. for 30 min beforewarming to RT. It was then poured into 10% HCl (100 mL). This mixturewas made basic with sat aq NaHCO₃ and extracted with ether. The aq layerwas reacidified and extracted with CH₂ Cl₂. The combined organic layerswere dried (MgSO₄), concentrated, and recrystallized to yield 4.2 g4-chloro-2-ethyl-1-hydroxy-1H-2,1-benzazaborol-3(2H)-one as a whitesolid. m.p. 210-211° C.

This compound (1.05 eq) in ethanol (2 mL) is added to an appropriatearyl, benzyl, or vinyl bromide (1 eq) and catalytictetrakis(triphenylphosphine)palladium(O) in toluene (20 mL) at RT undernitrogen. Sodium carbonate (4 mL of a 2M aq solution) was then added andthe resulting mixture was heated to reflux (4-24 h) and monitored byTLC. The mixture was then cooled to room temperature, diluted withadditional toluene (20 mL), filtered through celite/silica, washed withwater, dried (MgSO₄), and concentrated. If needed, the crude product waspurified by chromatography or recrystallization from ethylacetate/hexanes.

METHOD E1.

Amination of benzoyl chlorides.

A solution of the appropriate acid chloride (1 eq) in toluene or CH₂ Cl₂was added dropwise to an ice-water cooled solution of the appropriateamine (≧2 eq) in the same solvent. The mixture was stirred at RT for1-16 h until complete by GLC, then was partitioned between ethyl acetateand dilute aq acid. The organic phase was dried (MgSO₄) andconcentrated. If needed, the crude product was purified bychromatography, recrystallization or distillation.

METHOD E2.

Amination of benzoyl chlorides.

To a solution of the appropriate amine (>1 eq) in 50 mL CH₂ Cl₂ is addedan appropriate benzoyl chloride (1 eq) and a catalytic amount ofbenzyltriethylammonium chloride or pyridine. The mixture is cooled to 5°C. and ≧1 eq NaOH (50% aq) is added. The mixture is stirred from 3-16 h,washed with 10% HCl and water, dried and concentrated. The crude productis purified by chromatography, recrystallization or distillation toafford pure product.

Starting Materials Example a 2-Chloro-6-(trimethylsilyl)benzoic acid

2-Chlorobenzoic acid (3.91 g, 25 mmol), THF (60 mL), and TMEDA (8.6 mL,57 mmol) were stirred under nitrogen and cooled to -100° C. 1.3M s-BuLiin cyclohexane (0.055 mol, 42.3 mL) was added dropwise keeping thetemperature below -80° C. After the addition was complete, TMSCl (2.7 g,25 mmol) was added dropwise and the resulting mixture was allowed tostir and slowly warm to -30° C. 25% citric acid (100 mL) was added andthe mixture was extracted with two 50 mL portions of ether, which werethen combined and washed three times with water, dried (MgSO₄) andconcentrated. The crude product was purified by HPLC, eluting with 2:3ethyl acetate/hexanes. The product was recovered as a white solid in 63%yield. m.p. 129-131° C.

Example b 2-Chloro-6-(trimethylsilyl)benzoyl chloride

The compound of Example a (2.4 g, 0.01 mol), thionyl chloride (3.57 g,0.03 mol), toluene (50 mL), and 1 drop of DMF were stirred at RTovernight. The reaction mixture was twice concentrated under vacuum fromtoluene (50 mL) to afford the desired product as a brown oil in 100%yield.

Example c 2-Bromo-6-(trimethylsilyl)benzoic acid

2-Bromobenzoic acid (30.15 g, 150 mmol), THF (400 mL), and diisopropylamine (33.4 g, 330 mmol) were stirred under nitrogen and cooled to -78°C. 10M n-BuLi in hexanes (31 mL, 0.31 mol) was then added dropwise,followed by the dropwise addition of TMSCl (17.4 g, 160 mmol). Themixture was allowed to slowly warm to -30° C., stirred for 1 h, then waspoured into 25% citric acid (100 mL) and stirred for 15 min. The mixturewas extracted with two 100 mL portions of ether, which were combined andwashed three times with sat aq NaHCO₃ solution. The bicarbonate solutionwas acidified with 25% citric acid and extracted with three 100 mLportions of ether. These extracts were combined, dried (MgSO4), andconcentrated. The crude product was purified by recrystallization fromether/hexanes, and the desired product was recovered as a white solid in35% yield. m.p. 139-141° C.

Example d 2-Bromo-6-(trimethylsilyl)benzoyl chloride

The title compound was prepared from the compound of Example c accordingto the procedure of Example b.

Example e N,N-Diethyl-2-chlorobenzamide

2-Chlorobenzoyl chloride is reacted with diethylamine using GeneralMethod E1 or E2 to produce the title compound.

Example f N-Ethyl-2-chlorobenzamide

2-Chlorobenzoyl chloride is reacted with ethyl amine using GeneralMethod E1 or E2, to produce the title compound.

Example g (2-(2,6-difluorophenyl)-4,4-dimethyl-2-oxazoline

A solution of 2,6-difluorobenzoyl chloride (50 g, 283 mmol) in CH₂ Cl₂(200 mL) was added rapidly dropwise to an ice water-cooled solution of2-amino-2-methyl-1-propanol (63.1 g, 708 mmol) in CH₂ Cl₂ (400 mL). Theresulting mixture was stirred at RT and monitored to completion by GLC,then was extracted twice with 10% HCl and once with sat aq NaHCO₃. Theorganic phase was dried (MgSO₄), and concentrated to afford 61.9 gN-(1,1-dimethyl-2-hydroxyethyl)-2,6-difluorobenzamide as a white solid.

This compound (60 g, 283 mmol) was added portionwise to ice water-cooledthionyl chloride (65 mL). The resulting yellow solution was stirred atRT for 1 h, then was poured into stirred ether. The solid was collectedand washed with ether, then was partitioned between dilute aq NaOH andether. This latter ether extract was dried (MgSO₄) and concentrated toafford 52.39 g of the title compound as a white solid, an 88% yield.

Example h 2-Chloro-6-(trimethylsilyl)phenyl isocyanate

The compound of Example b (5.0 mmol) was dissolved in 50 mL acetonitrileand tetrabutylammonium azide (Bu₄ N₃) (5.2 mmol) was added. The mixturewas stirred at RT for 0.5 h. The solvent was removed and the resultingoil was dissolved in 100 mL toluene. After addition of 100 mL hexane aprecipitate was filtered off; the filtrate was concentrated to yield 1.5g of the title compound.

Example i 2-Chloro-6-(trimethylsilyl)benzaldehyde

A 2.0M solution of borane-dimethylsulfide in THF (100 mL) was added over15 min to a solution of the compound of Example a (11.4 g, 0.05 mol) THF(200 mL). The mixture was refluxed for two days, quenched with methanol(500 mL), and allowed to stand at RT for 2 days. The solvent was thenremoved and 2-chloro-α-hydroxy-6-(trimethylsilyl)toluene wasrecrystallized from hexane as 8.9 g of crystals, an 83% yield. m.p.40-42° C.

This compound (6.4 g, 29.9 mmol) was added to a solution of pyridiumchlorochromate (7.5 g) in CH₂ Cl₂ (500 mL). The mixture was stirred over2 days and ether (500 mL) was added. The mixture was filtered throughsilica gel and the solvent removed under vacuum. Again ether (200 mL)was added and the mixture filtered through silica gel. The solvent wasremoved to yield the title compound as 6.2 g of an oil, a 98% yield.

Example j 2-(2,6-difluorophenyl)-2-oxazoline

2,6-Difluorobenzoyl chloride (100 g, 566 mmol) was added dropwise over 2h to a vigorously stirred and ice water cooled mixture of 2-bromoethylamine hydrobromide (116.05 g, 566 mmol), benzyltriethylammonium chloride(5 g, 22.0 mmol), 10% aq NaOH (680 mL, 1.7 mol), and CH₂ Cl₂ (1.5 L).The resulting mixture was stirred at RT overnight, than was washed withwater (3×200 mL), dried (MgSO₄), concentrated, and kugelrohr distilledto afford 51.8 g of 2-(2,6-difluorophenyl)-2-oxazoline as a colorlessoil, a 50% yield.

Example k N-ethyl t-butylmethyleneimine

70% EtNH₂ (20.0 g, 310 mmol) was carefully added totrimethylacetaldehyde (24.35 g, 283 mmol) with ice-water cooling tocontrol the exotherm. When the exotherm ceased, the organic layer wasseparated and reacted with an additional 70% EtNH₂ (1-2 g). The organiclayer was separated and distilled (b.p. 96-98° C.) from CaH₂ to afford28.3 g of N-ethyl t-butylmethyleneimine as a colorless oil, an 88%yield.

Examples 1-4

These compounds are prepared as reported by Mills, et al., in "DirectedOrtho Metalation of N,N-Diethylbenzamides. Silicon Protection of OrthoSites and the o-Methyl Group," J. of Organic Chemistry 54: 4372-4385,1989.

    ______________________________________                                        Ex. No.     Compound                                                          ______________________________________                                        1           N,N-Diethyl-3-fluoro-6-methyl-2-                                                  (trimethylsilyl)benzamide                                       2             N,N-Diethyl-2-(trimethylsilyl)benzamide                         3             N,N-Diethyl-2-methyl-6-                                                       (trimethylsilyl)benzamide                                       4             N,N-Diethyl-3-fluoro-2-                                                       (trimethylsilyl)benzamide                                     ______________________________________                                    

Example 5N-(1,1-Dimethylethyl)-3-fluoro-N-methyl-2-(trimethylsilyl)benzamide

3-Fluorobenzoyl chloride was reacted with N-methyl-N-tert-butylamineusing General Method E1 or E2 to produceN-methyl-N-(tert-butyl)-3-fluorobenzamide. This compound was used inGeneral Method A to prepare the title compound. Kugelrohr distillationafforded 12.07 g of analytically pure desired material. m.p. 32-35° C.

Example 6 2-(1,1-Dimethylethyl)-N,N-diethyl-6-methylbenzamide

A 1.7M solution of t-BuLi in pentane (161 mL, 274 mmol) was addeddropwise to a solution of 2-(2-fluorophenyl)-4,4-dimethyl-2-oxazoline[cf. Meyers A. I. and Williams B. E., Tetrahedron Letters,223-226(1978)] (48.0 g., 249 mmol) in THF (320 mL), maintaining thereaction temperature between -45 and -40° C. with a dry-ice/acetonecooling bath. The resulting reaction mixture was maintained at ≦-40° C.with a dry-ice/acetonitrile bath, and monitored to completion by GLCover 20 min. This mixture was poured onto ice and extracted three timeswith ether. These extracts were combined, dried (MgSO₄), concentratedand distilled under vacuum to afford 56.87 g of2-(2-tert-butylphenyl)-4,4-dimethyl-2-oxazoline, a 93% yield.

A 2M solution of trifluoromethanesulfonic anhydride (1 eq) in CH₂ Cl₂was added dropwise to an ice water-cooled 0.67M solution of2-(2-tert-butylphenyl)-4,4-dimethyl-2-oxazoline (1 eq) in CH₂ Cl₂. Theresulting solution was stirred at 0° C. for 10 min, then poured into anequal volume of ice water and vigorously stirred for 15 min. The CH₂ Cl₂layer was washed twice with 10% HCl, dried (MgSO₄), and concentrated toafford 15.59 g ofN-[2-(2-tert-butylphenylcarboxy)-1,1-dimethylethyl]trifluoromethanesulfonamideas a white solid without any further purification, a 95% yield. m.p.69-71° C.

A freshly prepared solution of diazomethane in anhydrous ether was addedin excess to a solution ofN-[2-(2-tert-butylphenylcarboxy)-1,1-dimethylethyl]trifluoromethanesulfonamide(13.1 g) in ether. The resulting yellow solution was allowed to stand atRT overnight, then was washed with 10% HCl followed by 2.5N aq NaOH. Theorganic solution was dried (MgSO₄), and concentrated to afford 13.0 g ofpureN-methyl-N-[2-(2-tert-butylphenylcarboxy)-1,1-dimethylethyl]trifluoromethanesulfonamideas a white solid, a 96% yield. m.p. 42-44° C.

N-methyl-N-[2-(2-tert-butylphenylcarboxy)-1,1-dimethylethyl]trifluoromethanesulfonamide(1 eq) was saponified in a 2.0M solution of KOH (3 eq) in DMSO at 110°C. for 4 h. The resulting solution was cooled, diluted with water, andextracted twice with ether. These ether extracts were discarded. Theaqueous phase was then acidified to pH 1 with conc HCl and extractedtwice with ether. These latter ether extracts were dried (MgSO₄), andconcentrated to afford 4.47 g of 2-tert-butylbenzoic acid as pure whitesolid without any further purification, a 96% yield. m.p. 58-60° C.

A solution of 2-tert-butylbenzoic acid (4.0 g, 22.5 mmol) in thionylchloride (8.2 mL, 112 mmol) was stirred at RT for 2 h, then wasconcentrated three times from carbon tetrachloride to remove all tracesof excess thionyl chloride. A solution of diethylamine (4.93 g, 67.4mmol) in CH₂ Cl₂ (10 mL) was added dropwise over 10 min to an icewater-cooled solution of the crude acid chloride in CH₂ Cl₂ (35 mL). Tenmin after addition was complete, the reaction was partitioned betweenether and 10% HCl. The ether phase was then washed with sat aq NaHCO₃,then was dried (MgSO₄), and concentrated to afford a quantitative yieldof N,N-diethyl-2-tert-butylbenzamide as an off-white solid. m.p.38.5-40.5° C.

N,N-diethyl-2-tert-butylbenzamide (1.00 g, 4.3 mmol) was used in GeneralMethod A to afford 1.05 g of the title compound as a yellow oil, a 99%yield.

Example 7 2-Chloro-N,N-diethyl-6-(trimethylstannyl)benzamide

1.3M s-BuLi in cyclohexane (4.8 mL, 6.2 mmol) was added dropwise to a-78° C. cooled solution of the compound of Example e (1.0 g, 4.7 mmol)and TMEDA (930 μL, 6.2 mmol) in THF (15 mL). The resulting yellowmixture was stirred at -78° C. for 45 min, then was quenched by thedropwise addition of trimethyltin chloride (1.41 g, 7.1 mmol) in THF (5mL), maintaining the internal reaction temperature ≦-65° C. Theresulting green solution was warmed to RT to afford a yellow solutionwhich was diluted with ether and extracted twice with aq 10% HCl, andonce with sat aq NaHCO₃. The ether solution was dried (MgSO₄),concentrated, and purified by HPLC with 1:4 ethyl acetate/hexanes toafford 1.37 g of the title compound, an 81% yield, as a colorless oil.

Example 8 2-(1,1-Dimethylethyl)-N-ethyl-6-methylbenzamide

A solution of 2-tert-butyl-6-methylaniline (1 eq) and 97% formic acid (4eq) was refluxed for 16 h, then was concentrated under vacuum andrecrystallized from methanol/water to afford2-tert-butyl-6-methylformanilide.

Phosphorus oxychloride (0.67 eq) was added to an ice water-cooled,stirred slurry of this compound (1 eq) in a mixture of pyridine (11 eq=1volume) and pentane (0.5 volume). The resulting mixture was brieflywarmed to about 40° C. for 10 min, then the mixture was cooled. Icewater (0.5 volume) was carefully added and the two layers wereseparated. The aq layer was extracted with pentane (0.25 volume), thenthe combined organic solutions were washed three times with water (0.5volume), dried (MgSO₄), and concentrated to afford2-tert-butyl-6-methylphenyl isocyanide.

This compound was heated at 250-253° C. for 6 h to complete therearrangement as evidence by infrared analysis. Recrystallization fromhexanes afforded pure 2-tert-butyl-6-methylbenzonitrile. m.p. 60-62° C.

A solution of this compound (500 mg, 2.9 mmol) and 1.0M triethyloxoniumtetrafluoroborate in CH₂ Cl₂ (5.8 mL, 5.8 mmol) was stirred at RT forseveral days under an atmosphere of nitrogen. The reaction was dilutedwith CH₂ Cl₂ and extracted with sat aq NaHCO₃, then was dried (MgSO₄),concentrated, and purified by HPLC with 1:4 ethyl acetate/hexanes toafford 430 mg of title compound as a white solid, a 68% yield. m.p.110.5-111.5° C.

Example 92-[(1,1-Dimethylethyl)dimethylsilyl]-N,N-diethyl-3-fluorobenzamide.

1.3M s-BuLi in cyclohexane (7.7 mL, 0.01 mol) was added dropwise to THF(30 mL) and TMEDA (1.28 g, 0.011 mol) cooled to -78° C. under nitrogenwith stirring. To this mixture was added 0.0097 mol ofN,N-diethyl-3-fluorobenzamide (prepared from 3-fluorobenzoic acid anddiethylamine according to the procedures of the examples of b and f)dissolved in a minimum amount of THF dropwise. The mixture was stirredfor 10 min and injected with t-butyldimethylsilylchloride (3.01 g, 0.02mol). The reaction mixture was stirred and warmed to RT overnight. 25%citric acid (15 mL) was added and the mixture was extracted three timeswith ether. The ether extracts were combined and washed twice withwater, dried (MgSO₄), concentrated, and purified by RC eluting with 7:15ethyl acetate/hexanes. The title compound was recovered as a tan solidin 81% yield. m.p. 50-51° C.

Example 102-[(1,1-Dimethylethyl)dimethylsilyl]-N,N-diethyl-3-fluoro-6-methylbenzamide

1.3M s-BuLi in cyclohexane (1.8 mL, 2.3 mmol) was added dropwise withstirring to THF (20 mL) and TMEDA (0.32 g, 2.76 mmol), cooled to -78° C.under nitrogen. To this mixture was added dropwise the compound ofExample 9 (0.6 g, 2 mmol), dissolved in a minimum amount of THF. Afterstirring for 10 min, MeI (0.98 g, 6.9 mmol) was injected. The mixturewas stirred for 1 h; 15 mL of 25% citric acid was added and the mixtureextracted with ether 3 times. The ether extracts were combined andwashed twice with water, dried (MgSO₄), and concentrated. The crudeproduct was purified by RC, eluting with 3:7 ethyl acetate/hexanes. Thetitle compound was obtained as a light yellow oil in a 31% yield.

Example 11N-(1,1-Dimethylethyl)-3-fluoro-N,6-dimethyl-2-(trimethylsilyl)benzamide

1.3M s-BuLi in cyclohexane (31.4 mL, 41 mmol) was added dropwise to THF(100 mL) and TMEDA (5.35 g, 46 mmol), cooled to -100° C. under nitrogenwith stirring. To this mixture was added dropwise the compound ofExample 5 (10.45 g, 37 mmol), dissolved in a minimum amount of THF.After stirring for 10 min, MeI (15.8 g, 0.1114 mol) was injected. Themixture was stirred for 1 h and 25% citric acid (15 mL) was added. Themixture was extracted three times with ether; the ether extracts werecombined and washed twice with water, dried (MgSO₄), and concentrated.The crude product was purified by RC, with 1:9 ethyl acetate/hexanes.The title compound was recovered as a light yellow solid, in 99% yield.m.p. 44-47° C.

Example 12 N-Ethyl-3-fluoro-2-(trimethylsilyl)benzamide

N-ethyl-3-fluorobenzamide (4.18 g, 0.025 mol) (prepared from3-fluorobenzoic acid using the procedures of Examples b, and f),dissolved in a minimum amount of THF, was used in General Method C andpurified by HPLC, eluting with 3:7 ethyl acetate/hexanes. The titlecompound was recovered as a white solid in 53% yield. m.p. 80-82° C.

Example 13 N,N-Dipropyl-2-(trimethylsilyl)benzamide

N,N-(dipropyl)benzamide (4.0 g, 0.0195 mol) (prepared from benzoylchloride and dipropyl amine using General Method E1 or E2) was used inGeneral Method A to produce the desired compound which was purified byHPLC, eluting with 1:9 ethyl acetate/hexanes and recovered as a lightyellow oil in 65% yield. n_(D) ²⁵ =1.5094.

Example 14 2-Methyl-N,N-dipropyl-6-(trimethylsilyl)benzamide

The compound of Example 13 was reacted with MeI using General Method Ato prepare the title compound.

Example 15 3-Chloro-N,N-diethyl-2-(trimethylsilyl)benzamide

N,N-diethyl-3-chlorobenzamide (10.45 g, 50 mmol) (prepared from3-chlorobenzoic acid and diethylamine using the procedures describedabove) was reacted with TMSCl (16.30 g, 150 mmol) using General Method Ato afford 13.4 g of the title compound as an orange oil in 95% yield.

Examples 16-36

The following compounds were made by reaction of the compound of Exampleb with the appropriate amine using the procedures of General Method E1or E2, or similar procedures. The melting points of those which aresolids at ambient temperatures are reported as °C.

    ______________________________________                                        Example                       Physical                                          No.  Compound Name Property                                                 ______________________________________                                        16      2-Chloro-N-phenyl-6-(trimethylsilyl)-                                                               158-160                                                 benzamide                                                               17   2-Chloro-N-octyl-6-(trimethylsilyl)-       94-96                               benzamide                                                               18   2-Chloro-N-ethyl-N-(1-methylethyl)-6-      --                                  (trimethylsilyl)benzamide                                               19   2-Chloro-N-methyl-6-(trimethylsilyl)-     125-127                              benzamide                                                               20   N-Butyl-2-chloro-6-(trimethylsilyl)-      107-110                              benzamide                                                               21   2-Chloro-N-(1-methylethyl)-6-             140-143                              (trimethylsilyl)benzamide                                               22   2-Chloro-N-ethyl-N-methyl-6-     --                                            (trimethylsilyl)benzamide                                               23   2-Chloro-N-(1,1-dimethylethyl)-       --                                N-methyl-6-(trimethylsilyl)benzamide                                           24   2-Chloro-N-ethyl-N-phenyl-6-               95-98                               (trimethylsilyl)benzamide                                               25   2-Chloro-N-(2,2,2-trifluoro-              105-107                              ethyl)-6-(trimethylsilyl)-                                                    benzamide                                                               26   2-Chloro-N-propyl-6-                      108-109                              (trimethylsilyl)benzamide                                               27   2-Chloro-N-(2-hydroxyethyl)-6-            138-140                              (trimethylsilyl)benzamide                                               28   2-Chloro-N-(1-methylpropyl)-6-            144-145                              (trimethylsilyl)benzamide                                               29   2-Chloro-N-(2-chloroethyl)-6-           111.5-113                              (trimethylsilyl)benzamide                                               30   2-Chloro-N-(3-chloropropyl)-6-            128-131                              (trimethylsilyl)benzamide                                               31   2-Chloro-N-(phenylmethyl)-6-              112-114                              (trimethylsilyl)benzamide                                               32   2-Chloro-N-(2-furylmethyl)-6-             113-115                              (trimethylsilyl)benzamide                                               33   2-Chloro-N-(2-methylphenyl)-6-          116.5-118                              (trimethylsilyl)benzamide                                               34   2-Chloro-N-cyclopropyl-6-                 101-104                              (trimethylsilyl)benzamide                                               35   2-Chloro-N-ethyl-N-(phenylmethyl)-     --                                      6-(trimethylsilyl)benzamide                                             36   2-Chloro-N,N-dipropyl-6-      --                                               (trimethylsilyl)benzamide                                             ______________________________________                                    

Examples 37-39

The following compounds were prepared using General Method A or B. Thestarting materials are N,N-diethyl-3-fluorobenzamide, which is preparedfrom 3-fluorobenzoic acid as generally described above, and anappropriate electrophile.

    ______________________________________                                        Example                                                                         No.       Compound Name                      M.P.                           ______________________________________                                        37        6-Bromo-N,N-diethy1-3-f1uoro-                                                                    53.0-54.0                                                     2-(trimethylsilyl)benzamide                                        38         6-Chloro-N,N-diethyl-3-fluoro-2-                                              (trimethylsilyl)benzamide                                          39         2-Chloro-N,N-diethyl-6-                                                       (trimethylsilyl)benzamide                                        ______________________________________                                    

Example 40 N,N-Diethyl-3-fluoro-6-iodo-2-(trimethylsilyl)benzamide

4.99 g of the compound of Example 4 and 20.3 g iodine were combinedaccording to General Method B. The resulting reaction mixture was pouredinto ice water. CH₂ Cl₂ was added, and the mixture was extracted twicewith aq sodium thiosulfate to remove excess iodine. Then the organicsolution was extracted twice with brine, dried (MgSO₄), and concentratedto afford 5.6 g of the title compound as a yellow solid, a 77% yield.m.p. 58.5-64° C.

Example 41 N,N-Diethyl-3-fluoro-6-formyl-2-(trimethylsilyl)benzamide

5.34 g of the compound of Example 4 and 1.7 mL DMF were combinedaccording to General Method B. The resulting reaction mixture was pouredinto ice water. CH₂ Cl₂ was added, and the mixture was extracted with aqNaHCO₃, followed by brine, then was dried (MgSO₄), concentrated, andpurified by HPLC with 1:3 ethyl acetate/hexanes to afford 3.5 g of thetitle compound as a clear oil, a yield of 60%.

Example 42 2-[(Diethylamino)carbonyl]-4-fluoro-3-(trimethylsilyl)benzoicacid, methyl ester

20.06 g of the compound of Example 4 and excess CO₂ gas were combinedaccording to General Method A. The resulting reaction was poured intowater and acidified with 2N HCl. The solid which formed was collected byfiltration and dried to yield the corresponding acid.

A couple of drops of DMF were added to a mixture of this acid (9.34 g,30.0 mmol) and thionyl chloride (11.89 g, 100 mmol) in toluene (100 mL).The reaction was complete after 1 h at 70-74° C. The mixture wasconcentrated under vacuum to remove the excess thionyl chloride. Theresulting crude acid chloride (0.98 g, 3.0 mmol) was dissolved inmethanol (25 mL), and triethylamine (2 eq) was added dropwise. Afteraddition, the reaction was diluted with ethyl acetate and extracted withdilute aq HCl, then with sat aq NaHCO₃. The organic solution was dried(MgSO₄) and concentrated to afford 0.54 g of the title compound as asolid, a 55% yield. m.p. 46° C.

Example 43 2-[(Diethylamino)carbonyl]-4-fluoro-3-(trimethylsilyl)benzoicacid, 1-methylethyl ester

The acid chloride (0.98 g, 3.0 mmol) prepared as in Example 42 wasdissolved in isopropyl alcohol (25 mL), and triethylamine (1 mL, 7.0mmol) was added dropwise. After stirring overnight at ambienttemperature, the mixture was diluted with ethyl acetate and extractedwith dilute aq HCl, then with sat aq NaHCO₃. The organic solution wasdried (MgSO₄), concentrated, and purified by RC with 7:3 hexanes/ethylacetate to afford the title compound as a colorless oil.

Example 44 N,N,2-Triethyl-6-(trimethylsilyl)benzamide

The compound of Example 2 (2.49 g, 10 mmol) and ethyl iodide (4.68 g, 30mmol) were combined according to General Method B. The resultingreaction mixture was poured into ice water. Ether was added, and themixture was extracted with aq NaHCO₃ followed by brine, then was dried(MgSO₄) and concentrated to afford 2.83 g of the title compound as acolorless oil, a 100% yield.

Example 45 2-Chloro-N-ethyl-6-(trimethylsilyl)benzamide

The compound of Example f (2.2 g, 0.012 mol) was reacted with TMSCl(3.91 g, 0.036 mol) using General Method A. The title compound wasrecrystallized from ether/hexanes as a solid. m.p. 105-107° C.

Example 462-Chloro-N-ethyl-N-(methoxymethyl)-6-(trimethylsilyl)benzamide

A 2M THF solution of tert-butylmagnesium chloride (2.5 mL, 5 mmol) wasadded to an ice water cooled solution of the compound of Example 45(1.28 g, 5 mmol) in THF (25 mL). Chloromethyl methyl ether (0.44 g, 5.5mmol) was then added and the reaction mixture was stirred at ambienttemperature for 1 h and then partitioned between water and ethylacetate. The organic solution was dried (MgSO₄), concentrated, andpurified by RC with 1:9 ethyl acetate/hexanes to afford 0.80 g of thetitle compound as a colorless oil, a 53% yield.

Example 47 N-Acetyl-2-chloro-N-ethyl-6-(trimethylsilyl)benzamide

1M sodium bis(trimethylsilyl)amide in THF (5.5 mL, 5.5 mmol) was addeddropwise over several min to a solution of the compound of Example 45(1.28 g, 5 mmol) in THF (30 mL). The resulting mixture was cooled with awater bath while a solution of acetyl chloride (0.432 g, 5.5 mmol) inTHF (10 mL) was added, maintaining the internal reaction temperature.sup.˜ 25° C. After 1 h, the resulting reaction mixture was partitionedbetween sat aq NaHCO₃ and ether. The ether phase was dried (MgSO₄),concentrated, and purified by RC with 1:4 ethyl acetate/hexanes toafford 0.25 g of the title compound as a pale yellow oil, a 17% yield.

Example 48 N-Ethyl-2-methyl-6-(trimethylsilyl)benzamide

1.3M s-BuLi in cyclohexane (25.4 mL, 0.033 mol) was added dropwise toTHF (50 mL), TMEDA (3.83 g, 0.033 mol), and the compound of Example c(4.10 g, 0.015 mol), cooled to -78° under nitrogen with stirring. Afterstirring for 20 min, MeI (2.45 g, 0.01725 mol) was added all at once.The mixture was stirred for 1 h, and 25% citric acid (50 mL) was added.The mixture was extracted three times with CH₂ Cl₂. The combinedextracts were washed twice with water, dried (MgSO₄), and concentrated.To the resulting mixture were added 30 mL thionyl chloride and 5 dropsof DMF. After stirring at RT overnight, the mixture was concentrated todryness; 50 mL toluene were added; and again the mixture wasconcentrated. This process was repeated 3 times. The crude product, abrown oil, was dissolved in 30 mL toluene and added to a 100 mL solutionof 70% ethyl amine in water which had been cooled to 5° in an ice bath.After stirring overnight, the mixture was washed with 10% HCl and threetimes with water, dried (MgSO₄), concentrated, and purified by HPLCeluting with 1:3 ethyl acetate/hexanes. Two fractions were obtained.When each was concentrated, Compound 48 crystallized as a white solid ina 20% yield. m.p. 115-117° C. Compound 49 crystallized as a white solidin a 42% yield. m.p. 64-66° C.

Example 49 N-Ethyl-2-(trimethylsilyl)benzamide

N-Ethylbenzamide (74.5 g, 500 mmol) and TMSCl (135.8 g, 1.25 mol) werecombined according to General Method C and purified by HPLC with 1:4ethyl acetate/hexanes to afford 75.59 g of the title compound, as awhite solid, a 68% yield. m.p. 64.0-66.0° C.

Example 50 N-Ethyl-N-(methoxymethyl)-2-(trimethylsilyl)benzamide

A 1M THF solution of sodium bis(trimethylsilyl)amide (52.5 mL, 52.5mmol) was added dropwise over 5 min to a solution of the compound ofExample 49 (11.07 g, 50 mmol) in THF (100 mL). The resulting mixture wascooled with a dry ice/acetone bath while neat chloromethyl methyl ether(4.83 g, 60 mmol) was added, maintaining the internal reactiontemperature <-70° C. The cold bath was removed and the resultingreaction mixture was allowed to warm for 1 h, then was partitionedbetween sat aq NaHCO₃ and ether. The ether phase was dried (MgSO₄),concentrated, and purified by HPLC with 3:17 ethyl acetate/hexanes toafford 6.55 g of the title compound as a colorless oil, a 49% yield.

Example 51 N,N-Diethyl-2-methyl-6-(trimethylsilyl)thiobenzamide

A mixture of the compound of Example 3 (2.0 g, 7.6 mmol) and Lawesson'sreagent (2.3 g, 5.7 mmol) in xylenes (50 mL) was refluxed for 16 h, thenwas cooled, and filtered. The filtrate was partitioned between ether andwater. The organic layer was washed with 10% HCl and brine, dried(MgSO₄), and concentrated. The crude product was purified by RC usingwith 1:9 ethyl acetate/hexanes to afford 1.4 g of the title compound asa yellow oil, which crystallized upon standing, a 66% yield. m.p. 82-83°C.

Example 52N,N-Diethyl-6-(difluoromethyl)-3-fluoro-2-(trimethylsilyl)benzamide

To a solution of DAST (55 mg, 0.34 mmol) in 1 mL CH₂ Cl₂ at 0° C. wasadded the compound of Example 41 (100 mg, 0.34 mmol). The solution wasrefluxed for 16 h and a second molar equivalent of DAST was added. Thisprocedure was continued until the reaction was complete by GC analysis.The mixture was poured onto 10 g of ice and the aq solution wasextracted with CH₂ Cl₂. The extracts were combined, washed with brine,dried (MgSO₄), and concentrated. The product was purified by RC usingwith 1:9 ethyl acetate/hexanes to give 800 mg of the title compound as ayellow solid, a 92% yield. m.p. 65-67° C.

Example 53 N,N-Diethyl-3-fluoro-6-methyl-2-(trimethylsilyl)thiobenzamide

The title compound was prepared from the compound of Example 1 andLawesson's reagent according to the procedure for Example 51. The crudeproduct was flash chromatographed on a 6" silica gel column with 1:19ethyl acetate/hexanes and then recrystallized from hexanes to give 820mg of the title compound as a white solid, a 78% yield. m.p. 68-69° C.

Example 54N,N-Diethyl-3-fluoro-6-(hydroxymethyl)-2-(trimethylsilyl)benzamide

The compound of Example 41 (1.2 g, 4.1 mmol) and sodium borohydride (200mg, 5.3 mmol) in ethanol (20 mL) were stirred at ambient temperature for2 h. The solution was concentrated and partitioned between ether and 10%citric acid. The ether layer was washed with water and then brine, dried(MgSO₄), concentrated, and recrystallized from cold hexanes to afford1.0 g of the title compound, an 82% yield. m.p. 107-108° C.

Example 55N,N-Diethyl-3-fluoro-6-(fluoromethyl)-2-(trimethylsilyl)benzamide

A solution of DAST (400 mg, 2.5 mmol) and the compound of Example 54(660 mg, 2.2 mmol) in CH₂ Cl₂ (30 mL) was stirred for 2 h at 25° C. Thesolution was poured into ice water (50 mL) and extracted with CH₂ Cl₂.The organic extracts were combined, washed with brine, dried (MgSO₄),concentrated, and purified by RC with 1:9 ethyl acetate/hexanes to give550 mg of the title compound as a yellow oil, an 83% yield.

Example 56 N,N-Diethyl-3,6-difluoro-2-(trimethylsilyl)benzamide

Diethyl amine (15.4 g, 210 mmol) and 2,5-difluorobenzoyl chloride (17.6g, 100 mmol) were reacted using General Method E1 to afford 20.0 g ofN,N-diethyl-2,5-difluorobenzamide as a clear oil, a 94% yield.

The title compound was prepared from this compound and 2.0 eq TMSClaccording to General Method A. The crude product was purified by HPLCwith 1:9 ethyl acetate/hexanes to give 4.8 g of the desired product as aclear oil, an 84% yield.

Example 57 N,N-Diethyl-3-fluoro-4-methyl-2-(trimethylsilyl)benzamide

1.3M s-BuLi (9.2 mL, 12 mmol) was added dropwise to a -78° C. cooledsolution of the compound of Example 4 (3.48 g, 10 mmol) and TMEDA (1.8mL, 12 mmol) in THF. The reaction mixture was warmed to -60° C., stirredfor 3 h, cooled to -78° C., and MeI (5.0 g, 36 mmol) was added. After aninitial exotherm to -58° C., the reaction mixture was allowed to warm to0° C. and worked up in the usual manner. The crude product was purifiedby HPLC with 1:4 ethyl acetate/hexanes to give 300 mg of the titlecompound as a clear oil, a 71% yield.

Example 58 N,N-Diethyl-4-methyl-2-(trimethylsilyl)benzamide

N,N-Diethyl-4-methylbenzamide was prepared from 4-methylbenzoyl chlorideand diethylamine according to General Method E1. The crude product wasrecrystallized from cold hexanes to give 30.4 g of the desired compoundas a white solid, a 98% yield. m.p. 54° C.

The title compound was prepared from this compound and 3.0 eq TMSClaccording to General Method A. The crude product was purified by HPLCwith 3:17 ethyl acetate/hexanes to give 7.0 g of the title compound as aclear oil, an 89% yield.

Example 59 N,N-Diethyl-2-chloro-4-methyl-6-(trimethylsilyl)benzamide

The title compound was prepared from the compound of Example 58 and 1.2eq hexachloroethane according to General Method A. Purification by HPLCwith 1:9 ethyl acetate/hexanes afforded 1.6 g of the title compound as aclear oil, a 54% yield.

Example 60 N,N-Diethyl-2,4-dimethyl-6-(trimethylsilyl)benzamide

The title compound was prepared from the compound of Example 58 and MeI(4.0 eq) according to General Method A. Purification by HPLC with 3:17ethyl acetate/hexanes gave 1.4 g of the title compound as a clear oil,an 83% yield.

Example 61 N,N-Diethyl-2-(trimethylsilyl)-6-(trifluoromethyl)benzamide

N,N-Diethyl-2-(trifluoromethyl)benzamide was prepared from2-trifluoromethylbenzoyl chloride and diethylamine according to GeneralMethod E1. No purification was needed to obtain 17.2 g of this compound,a 97% yield.

The title compound was prepared from this compound and 3.0 eq TMSClaccording to General Method A. The crude material was purified by HPLCwith 3:17 ethyl acetate/hexanes to afford 2.7 g of the title compound asa clear oil, an 85% yield.

Example 62N,N-Diethyl-2-(trimethylsilyl)-3,6-bis(trifluoromethyl)benzamide

N,N-Diethyl-2,5-bis(trifluoromethyl)benzamide was prepared from2,5-bis(trifluoromethyl)benzoyl chloride and diethylamine according toGeneral Method E1. The desired intermediate was isolated in quantitativeyield (11.3 g) without additional purification.

The title compound was prepared from this compound and 3.7 eq TMSClaccording to General Method A. Purification by HPLC with 1:19 ethylacetate/hexanes, followed by kugelrohr distillation (90° C. @ 0.1 mm Hg)afforded 2.0 g of the title compound as a white solid, a 52% yield. m.p.55-56° C.

Examples 63 and 64 Compound 63:N,N-Diethyl-5-methyl-2-(trimethylsilyl)benzamide Compound 64:N,N-diethyl-3-methyl-2-(trimethylsilyl)benzamide

These compounds were prepared from N,N-diethyl-3-methylbenzamide and 2.0eq TMSCl according to General Method A. Purification by HPLC using 1:9ethyl acetate/hexanes gave two products. Compound 63 was isolated as 6.0g of a clear oil, a 46% yield. Compound 64 was isolated as 2.3 g of aclear oil, a 17% yield.

Example 65 N,N-Diethyl-2-chloro-3-methyl-6-(trimethylsilyl)benzamide

The title compound was prepared according to General Method A from thecompound of Example 63 and 1.3 eq hexachloroethane. Purification by RCusing 1:4 ethyl acetate/hexanes gave 500 mg of the title compound as ayellow solid, a 44% yield. m.p. 42-44° C.

Example 66 N,N-Diethyl-2-chloro-6-(triethylsilyl)benzamide

The title compound was prepared according to General Method A from thecompound of Example e and 1.4 eq chlorotriethylsilane. Purification byHPLC with 1:19 ethyl acetate/hexanes gave 6.0 g of the desired productas a clear oil, a 92% yield.

Example 67 N,N-Diethyl-2-chloro-6-(dimethylphenylsilyl)benzamide

The title compound was prepared from the compound of Example e and 1.1eq dimethylphenylsilyl chloride according to General Method A.Purification by HPLC with 1:9 ethyl acetate/hexanes gave 6.3 g of thedesired product as a clear oil, a 91% yield.

Example 68 N,N-Diethyl-2-chloro-6-[tris(1-methylethyl)silyl]benzamide

The title compound was prepared according to General Method A from thecompound of Example e and 1.1 eq triisopropylsilyl chloride.Purification by HPLC using 1:19 ethyl acetate/hexanes gave 5.5 g of thedesired product as of a clear oil, a 75% yield.

Example 69 N,N-Diethyl-2-chloro-6-[(chloromethyl)dimethylsilyl]benzamide

The title compound was prepared according to General Method A from thecompound of Example e and 1.5 eq (chloromethyl)dimethylsilyl chloride.Purification by HPLC using 1:9 ethyl acetate/hexanes gave 5.4 g of thedesired compound as a yellow oil, an 85% yield.

Example 70 N-Ethyl-2-(trimethylsilyl)-3-thiophenecarboxamide

A mixture of thiophene-3-carboxylic acid (20.0 g, 178 mmol), thionylchloride (30 mL, 411 mmol), and catalytic DMF (5 drops) was stirred atRT overnight. This solution was concentrated under vacuum, and strippedseveral times from toluene to remove all traces of excess thionylchloride. Ethyl amine hydrochloride (29.03 g, 356 mmol) was then addedto a solution of this crude acid chloride dissolved in CH₂ Cl₂ (50 mL).Pyridine (31.64 g, 400 mmol) was added, and after 1 h of stirring thereaction was washed with 10% HCl followed with water, dried (MgSO₄),concentrated, and recrystallized from EtOAc/hexanes to give 14.9 g ofN-ethyl-3-thiophenecarboxamide as a tan solid, a 76% yield. m.p.115-117° C.

1.3M s-BuLi in cyclohexane (37.23 mL, 48.4 mmol) was added dropwise to adry-ice/acetone cooled solution of N-ethyl-3-thiophenecarboxamide (3.41g, 22 mmol) and TMEDA (5.62 g, 48.4 mmol) in THF (100 mL). Afterstirring for 30 min at -78° C., TMSCl (5.26 g, 48.4 mmol) was added in asingle portion. The reaction was allowed to slowly warm to -10° C. over1 h, then was quenched with dilute aq citric acid and extracted withethyl acetate (3×). The combined organic solutions were dried (MgSO₄),concentrated, and purified by HPLC with 3:7 EtOAc/hexanes to give 1.4 gof the title compound as a white solid, a 28% yield. m.p. 114-116° C.

Example 71 N,N-Diethyl-6-chloro-3-methyl-2-(trimethylsilyl)benzamide

The title compound was prepared according to General Method A from thecompound of Example 64 and 1.1 eq hexachloroethane. Purification by HPLC1:9 ethyl acetate/hexanes gave 1.5 g of an oil which crystallized uponstanding, an 83% yield. m.p. 36-37° C.

Example 72 3-Chloro-N-ethyl-2'-methyl-[1,1'-biphenyl]-2-carboxamide

The title compound was prepared according to General Method D exceptthat 1-butanol instead of CH₂ Cl₂ was used to extract the boronintermediate. The crude intermediate was further reacted with2-bromotoluene as described in General Method D to give the titlecompound as a white solid (recrystallized from toluene) in 55% overallyield. m.p. 131-134° C.

Example 73 2-Chloro-N-ethyl-6-(1-naphthalenyl)benzamide

The title compound was prepared from the compound of Example f and1-bromonaphthalene (0.76 g, 3.65 mmol) according to General Method D. Itwas obtained as 0.28 g of a white solid, a 28% yield. m.p. 181-182° C.

Example 74 N,N-Diethyl-3-fluoro-2-(trimethylsilyl)thiobenzamide

A mixture of N,N-diethyl-3-fluorobenzamide (4.69 g, 24 mmol) (cf Mills,et al., "Directed Ortho Metalation of N,N-Diethylbenzamides. SiliconProtection of Ortho Sites and the o-Methyl Group," J. of OrganicChemistry 54: 4372-4385, 1989), Lawesson's reagent (6.47 g, 16 mmol) andxylenes (150 mL) was refluxed overnight, then was concentrated andkugelrohr distilled (105-110° C. at 0.25 torr) to yield 4.8 gN,N-diethyl-3-(fluoro)thiobenzamide as a yellow oil, a 95% yield.

This compound and 1.8 eq TMSCl were combined according to General MethodA and purified by HPLC with 1:9 ethyl acetate/hexanes to give 3.7 g ofthe title compound as a yellow solid, a 77% yield. m.p. 71-73° C.

Example 75 N,N-Diethyl-3-fluoro-4-methyl-2-(trimethylsilyl)thiobenzamide

The title compound was prepared from the compound of Example 74 and 3.0eq MeI according to General Method A and recrystallized from coldhexanes/ethyl acetate to give 2.5 g of the title compound, an 82% yield.m.p. 96-97° C.

Example 76 2-Chloro-N-ethyl-6-(trimethylsilyl)thiobenzamide

The title compound was prepared from the compound of Example 45 usingthe procedure of Example 51. m.p. 158.0-159.0° C.

Example 77 2-Chloro-6-(trimethylsilyl)benzenecarbothioic acid, S-ethylester

The compound of Example b (1.48 g, 0.006 mol), CH₂ Cl₂ (50 mL),ethanethiol (0.44 g, 0.007 mol), and 4-(N,N-dimethylamino)pyridine (0.86g, 0.007 mol) were allowed to stir at RT overnight. The mixture waswashed with 10% HCl and three times with water, dried (MgSO₄), andconcentrated. The crude product was purified by RC, eluting with 1:3ethyl acetate/hexanes. The title compound was obtained as a clear oil in61% yield.

Examples 78-81

The following compounds were prepared as in Example 77 using theappropriate thiol ester in the yields shown.

    ______________________________________                                        Ex. No.    Compound Name    Yield                                             ______________________________________                                        78         2-Chloro-6-(trimethylsilyl)-                                                                   35%                                                             benzenecarbothioic acid, S-(1-                                                methylethyl)ester                                                 79         2-Chloro-6-(trimethylsilyl)-        80%                                        benzenecarbothioic acid, S-                                                   propyl ester                                                      80         2-Chloro-6-(trimethylsilyl)-        47%                                        benzenecarbothioic acid, S-(1-                                                methylpropyl)ester                                                81         2-Chloro-6-(trimethylsilyl)-        81%                                        benzenecarbothioic acid, S-(2-                                                methylpropyl)ester                                              ______________________________________                                    

Example 82 N-Ethyl-2-(trifluoromethyl)-6-(trimethylsilyl)benzamide

2-(Trifluoromethyl)benzoyl chloride and ethyl amine were combinedaccording to General Method E1 and recrystallized from cold hexanes togive 7.7 g N-ethyl-2-(trifluoromethyl)benzamide as a white solid, a 67%yield. m.p. 73-76° C.

This compound was combined with 2.0 eq TMSCl according to General MethodC. Recrystallization from ethyl acetate/hexanes gave 2.0 g of the titlecompound as a white solid, a 69% yield. m.p. 134-135° C.

Example 83 N-Ethyl-2-chloro-6-[(chloromethyl)dimethylsilyl]benzamide

The title compound was prepared from the compound of Example f and 2.0eq (chloromethyl)dimethylsilyl chloride according to General Method C.Recrystallization from ethyl acetate gave 3.0 g of the desired compoundas a white solid, a 52% yield. m.p. 88-89° C.

Example 84 N,N-Diethyl-2,3-dichloro-6-(trimethylsilyl)benzamide

The title compound was prepared from the compound of Example 39 and 1.5eq hexachloroethane according to General Method A. Purification by RCwith 1:4 ethyl acetate/hexanes afforded 320 mg of the desired compoundas a white solid, a 14% yield. m.p. 143-147° C.

Example 85 N,N-Diethyl-2-chloro-3-ethyl-6-(trimethylsilyl)benzamide

The title compound was prepared from the compound of Example 39 and 8.5eq ethyl iodide according to General Method A. Purification by RC with1:4 ethyl acetate/hexanes gave 1.3 g of the desired compound as a greenoil, a 57% yield.

Example 86 N,N-Diethyl-2-chloro-3,6-bis(trimethylsilyl)benzamide

The title compound was prepared from the compound of Example 39 and 2.0eq TMSCl according to General Method A. Purification by HPLC with 1:4ethyl acetate/hexanes gave 0.9 g of the title compound as a white solid,a 37% yield. m.p. 93-96° C.

Example 87 N-Ethyl-2-chloro-6-(ethenyldimethylsilyl)benzamide

The title compound was prepared from the compound of Example f and 1.5eq vinyldimethylsilyl chloride according to General Method C.Purification by HPLC with 1:4 ethyl acetate/hexanes gave 630 mg of thedesired product as a white solid, a 9% yield. m.p. 86-89° C.

Example 88 N,N-Diethyl-2-chloro-3-fluoro-6-(trimethylsilyl)benzamide

N,N-Diethyl-2-chloro-3-fluorobenzamide was prepared fromN,N-diethyl-3-fluorobenzamide (prepared from 3-fluorobenzoic acid anddiethyl amine as generally described above) and 1.4 eq hexachloroethaneaccording to General Method A. Purification by HPLC WITH 1:4 ethylacetate/hexanes gave 3.3 g of the desired compound as a clear oil, a 56%yield.

This compound was combined with 2.0 eq TMSCl according to General MethodA. Purification by HPLC with 3:7 ethyl acetate/hexanes gave 2.2 g of thetitle compound as a clear oil, a 50% yield.

Example 89 N-Ethyl-2-chloro-6-(1,1-dimethylethoxy)benzamide

To a solution of the compound of Example f (3.7 g, 20 mmol) and TMEDA(6.0 mL, 40 mmol) in anhydrous THF (100 mL) at -78° C. under nitrogenwas added dropwise 1.3M s-BuLi (34 mL, 44 mmol). After 30 min MgBr₂.Et₂O (15.5 g, 60 mmol) was added, and the solution was warmed to ambienttemperature, then cooled to -78° C. and stirred for 1 h. t-Butylperoxybenzoate (4.3 g, 22 mmol) was added, and the solution was warmed to -30°C. and worked up in the usual manner. Purification by HPLC with 3:17ethyl acetate/hexanes gave 1.7 g of the desired compound as a whitesolid, a yield of 33%. m.p. 126-127° C.

Example 90 2-[1,1-Dimethylethyl)thio]-N-ethyl-6-fluorobenzamide

A solution of 2-methyl-2-propanethiol (2.7 g, 0.03 mol), THF (100 mL),sodium hydride (0.79 g, 0.033 mol), and the compound of Example g (3.17g, 0.015 mol), were stirred at RT overnight followed by refluxingovernight. The mixture was allowed to cool and sat aq NaHCO₃ (50 mL) wasadded. This mixture was extracted with three 50 mL portions of ethylacetate. The organics were combined and washed twice with water, dried(MgSO₄) and concentrated. The concentrate was purified by HPLC, elutingwith 1:4 ethyl acetate/hexanes. This oxazoline compound was obtained asa yellow oil in 83% yield.

This product was then carried through Steps 1, 2, 3, and 4, as follows:

Step 1, Oxazoline Ring Opening:

A 2M solution of trifluoromethanesulfonic anhydride (1.5 eq) in CH₂ Cl₂was added dropwise to an ice water-cooled 0.67M solution of theoxazoline compound (1 eq) in CH₂ Cl₂. The resulting solution was stirredat 0° C. for 1 min, then was poured into an equal volume of ice-waterand vigorously stirred for 15 min. The organic layer was washed twicewith 10% HCl, dried (MgSO₄), and concentrated. Purification by HPLC inethyl acetate/hexanes over silica was accomplished.

Step 2, Methylation with Diazomethane:

A freshly prepared solution of diazomethane in anhydrous ethyl ether wasadded in excess to an ether solution of the product from Step 1. Theresulting yellow solution was allowed to stand at RT overnight beforebeing quenched with acetic acid (5 mL). The organic layer was thenwashed with 10% HCl followed by 2.5N aq NaOH, dried (MgSO₄), andconcentrated to afford the N-methylated sulfonamide.

Step 3, Saponification of N-Methylated Sulfonamide:

Potassium hydroxide (3 eq) and the N-methylated sulfonamide from Step 2in DMSO were stirred at 110° C. for 3-4 h. The resulting solution wascooled, diluted with an equal volume of water, and extracted three timeswith ether. The aqueous layer was then acidified with 10% HCl andextracted three times with ether. The latter extracts were combined,dried (MgSO₄), and concentrated to yield the 2,6-disubstituted-benzoicacid.

Step 4, Preparation of 2,6-Disubstituted-N-Ethyl-Benzamide:

Oxalyl chloride (2.2 eq) and the 2,6-disubstituted-benzoic acid (1 eq)from Step 3 were stirred in toluene with catalytic DMF at RT undernitrogen for 1 h. The solvent was removed in vacuo before additionaltoluene (50 mL) was added and similarly removed. The resulting acidchloride was dissolved in CH₂ Cl₂ (50 mL) treated with 70% ethyl amine(3.3 eq) and stirred an additional 30 min at RT. The organic layer wasthen washed twice with 10% HCl and twice with water, dried (MgSO₄), andconcentrated to yield a white solid. Purification was byrecrystallization from ether/ hexanes. The resulting final product wasrecrystallized from ether/hexanes. The title compound was recovered as awhite solid. m.p. 107-109° C.

Example 93 2-(2,2-Dimethylpropyl)-N-ethyl-6-fluorobenzamide

A solution of p,p'-di-t-butyl biphenyl (5.559 g, 0.021 mol) and THF (100mL) was stirred at 0° C. under an atmosphere of argon. Lithium wire(0.021 mol, 0.15 g) was added in small pieces and the mixture wasallowed to stir at 0° C. for 24 h. The mixture was cooled to -78° C. andneopentyl chloride (2.0 g, 0.01875 mol) was added dropwise. The mixturewas stirred at -78° C. for 1 h, and the compound of Example g (3.17 g,0.015 mol) was added all at once. The mixture was continuously stirredor 4 h and 50 mL sat aq NaHCO₃ was added. This mixture as extracted withthree 50 mL portions of ethyl acetate. The combined extracts were washedtwice with water, dried (MgSO₄), and concentrated. The crude concentratewas purified by HPLC eluting with 1:4 ethyl acetate/hexanes. Theoxazoline was as a clear oil in 27% yield.

This product was then carried through Steps 1-4 of Example 90. Theresulting final product was recrystallized from ether/hexanes. The titlecompound was obtained as a white solid. m.p. 125-126° C.

Example 94 N-Ethyl-2-fluoro-6-(2-methylphenyl)benzamide

A solution of 2-bromotoluene (2.82 g, 0.0165 mol) and THF (100 mL) wasstirred magnetically under argon at -78° C. 1.3M s-BuLi in cyclohexane(0.018 mol, 13.85 mL) was added dropwise. The mixture was stirred for0.5 h and the compound of Example g (3.17 g, 0.015 mol) was added all atonce. The mixture was continuously stirred for 4 h and sat aq NaHCO₃ (50mL) was added. The mixture was extracted with three 50 mL portions ofethyl acetate. The combined extracts were washed twice with water, dried(MgSO₄), and concentrated. The concentrate was purified by HPLC, elutingwith 1:4 ethyl acetate/hexanes. The oxazoline was obtained as a clearoil in 73% yield.

This product was then carried through Steps 1-4 of Example 90. Theresulting final product was recrystallized from ether/hexanes. The titlecompound was obtained as a white solid. m.p. 75-77° C.

Example 952-Chloro-N-(1-methylethyl)-N-propyl-6-(trimethylsilyl)benzamide

A solution of propionyl chloride (23.13 g, 250 mmol) in ether (100 mL)was added dropwise to an ice water-cooled solution of iso-propylamine(29.56 g, 500 mmol) in ether (200 mL). The resulting mixture was stirredat RT for 1 h, then was filtered to remove iso-propylaminehydrochloride. The solution of N-iso-propylpropionamide (37% of thefiltrate, .sup.˜ 92 mmol) was diluted with THF (90 mL) and cooled withan ice water bath while a 2M THF solution of borane-dimethylsulfide (100mL, 200 mmol) was added dropwise. The resulting solution was stirred atRT for 1 h, then was refluxed for 2 h. With ice-water cooling, theexcess borane-dimethylsulfide was quenched by the dropwise addition ofmethanol (30 mL), and the mixture was allowed to stand at RT overnight.HCl gas was bubbled into the solution, and theN-propyl-N-iso-propylamine hydrochloride was collected.

Triethylamine (27.89 mL, 200 mmol) was added to a mixture of thecompound of Example b (2.47 g, 10 mmol) and N-propyl-N-iso-propylaminehydrochloride (.sup.˜ 92 mmol) in toluene (100 mL). The reaction wasstirred overnight at ambient temperature, then was partitioned betweenethyl acetate and dilute citric acid. The organic phase was washed withbrine, dried (MgSO₄), and concentrated to afford 2.50 g of the titlecompound as a waxy amber solid, an 80% yield.

Example 962-Chloro-N-ethyl-N-(1-methylheptyl)-6-(trimethylsilyl)benzamide

A solution of acetyl chloride (7.11 mL, 100 mmol) was added dropwise toan ice water-cooled solution of 1-methylheptyl amine (8.30 g, 64 mmol)and triethylamine (20.91 mL, 150 mmol) in THF (100 mL). The resultingmixture was stirred at RT for 1 h, then was diluted with ethyl acetateand washed twice with 10% HCl, twice with sat aq NaHCO₃, and then twicewith brine. The organic solution was dried (MgSO₄), and concentrated toafford 8.13 g N-(1-methylhept-1-yl)acetamide, a 73% yield.

A 2M THF solution of borane-dimethylsulfide (31.5 mL, 63 mmol) was addeddropwise to an ice water-cooled solution ofN-(1-methylhept-1-yl)acetamide (5.13 g, 30 mmol) in THF (60 mL). Theresulting solution was stirred at RT for 1 h, then was refluxedovernight. With ice-water cooling, the excess borane-dimethylsulfide wasquenched by the dropwise addition of methanol (10 mL), and the mixturewas allowed to stand at RT overnight. The amine hydrochloride could notbe precipitated with the addition of HCl gas, so the amine hydrochloridewas extracted into dilute HCl. The acidic aq solution was extracted withether, then made basic and extracted with ethyl acetate. The ethylacetate solution was dried (MgSO₄) and concentrated to afford 3.70 g ofimpure N-ethyl-N-(1-methylhept-1-yl)amine as an amber oil.

Triethylamine (2.02 g, 20 mmol) was added to a mixture of the compoundof Example b (2.47 g, 10 mmol) and N-ethyl-N-(1-methylhept-1-yl)amine(3.15 g, 20 mmol) in toluene (25 mL). The reaction was stirred 2.5 h atambient temperature, then was partitioned between ethyl acetate anddilute citric acid. The organic phase was washed twice with sat aqNaHCO₃, followed with brine, then was dried (MgSO₄), concentrated, andkugelrohr distilled under vacuum. The fraction which distilled at 157°C. was collected to afford 1.16 g of the title compound as an amber oil,a 38% yield.

Example 97 2-(Difluoromethyl)-N,N-diethyl-6-(trimethylsilyl)benzamide

The compound of Example 2 (9.96 g, 40 mmol) and a solution of DMF (3.65g, 50 mmol) in THF (20 mL) were combined according to General Method A.The resulting reaction mixture was partitioned between ethyl acetate anddilute citric acid. The organic phase was washed with sat aq NaHCO₃followed with brine, dried (MgSO₄), and concentrated to afford 8.35 g ofN,N-diethyl-2-trimethylsilyl-6-formylbenzamide as a white solid, a 75%yield. m.p. 63.5-65.5° C.

DAST (0.63 mL, 4.8 mmol) was added to an ice water-cooled solution ofN,N-diethyl-2-trimethylsilyl-6-formylbenzamide (0.665 g, 2.4 mmol) inCH₂ Cl₂ (20 mL). The solution was warmed to RT and stirred for 17 h,then additional DAST (1.0 mL, 7.6 mmol) was added. This mixture wasstirred for 1 additional day, then was quenched with ice-water. The CH₂Cl₂ solution was dried (MgSO₄) and concentrated to afford 0.69 g of thetitle compound as an amber oil, a yield of 96%.

Example 98 N,N-Diethyl-2-(fluoromethyl)-6-(trimethylsilyl)benzamide

Sodium borohydride (1.0 g, 26.4 mmol) was added to a solution ofN,N-diethyl-2-trimethylsilyl-6-formylbenzamide, prepared in Example 97,(5.54 g, 20 mmol) in absolute ethanol (100 mL). After 3 h the mixturewas diluted with ether, extracted three times with brine, dried (MgSO₄),concentrated, and recrystallized from 1:1 ethyl acetate/hexanes toafford 4.12 g of N,N-diethyl-2-trimethylsilyl-6-hydroxymethylbenzamideas a white solid, a 74% yield. m.p. 81-82.5° C.

DAST (0.66 mL, 5.0 mmol) was added to an ice water-cooled solution ofthis compound (1.395 g, 5.0 mmol) in CH₂ Cl₂ (40 mL). The solution waswarmed to RT and stirred for 4 h, then was quenched with ice-water andextracted with CH₂ Cl₂. The CH₂ Cl₂ extracts were combined, dried(MgSO₄), and concentrated to afford 1.38 g of the title compound as anamber oil, a 98% yield.

Example 99 2-Chloro-6-(trimethylsilyl)-2,2-dimethylhydrazidebenzoic acid

A solution of the compound of Example b (1.48 g, 0.006 mol), CH₂ Cl₂ (50mL), 1,1-(dimethyl)hydrazine (0.42 g, 0.007 mol), and pyridine (0.55 g,0.007 mol) was allowed to stir at RT overnight. The reaction mixture waswashed with 10% HCl and three times with water, dried (MgSO₄), andconcentrated. The title compound was recrystallized as a white solid in43% yield. m.p. 134-135° C.

Examples 101-108

The following examples were prepared by reaction of the compound ofExample b and the appropriate amine by refluxing in toluene or byovernight ambient temperature reaction in dioxane in the presence of anacid scavenger such as triethylamine. The melting points are reported in°C.

    ______________________________________                                        Ex. No.   Compound Name     M.P.                                              ______________________________________                                        101       2-Chloro-N-[[4-(1,1-                                                                            --                                                              dimethylethyl)phenyl)methyl]-                                                 N-methyl-6-(trimethylsilyl)-                                                  benzamide                                                         102        2-Chloro-N-[[4-                    159-160                                     (trifluoromethyl)phenyl]-                                                     methyl]-6-(trimethylsilyl)-                                                   benzamide                                                         103        2-Chloro-N-methyl-N-[[4-           85-86                                       (trifluoromethyl)phenyl]-                                                     methyl]-6-(trimethylsilyl)-                                                   benzamide                                                         104        2-Chloro-N-(6,6-dimethyl-2-            --                                      hepten-4-ynyl)-N-ethyl-6-                                                     (trimethylsilyl)benzamide                                         105        2-Chloro-N-methyl-N-(3-phenyl-         --                                      2-propenyl)-6-                                                                (trimethylsilyl)benzamide                                         106        2-Chloro-N-2-propenyl-6-               97-99                                   (trimethylsilyl)benzamide                                         107        2-Chloro-N-(1,1-dimethyl-2-            155-157                                 propynyl)-6-                                                                  (trimethylsilyl)benzamide                                         108        2-Chloro-N-(2-propynyl)-6-             112-114                                 (trimethylsilyl)benzamide                                       ______________________________________                                    

Example 109 [2-Chloro-6-(trimethylsilyl)phenyl]carbamic acid, ethylester

A mixture of the compound of Example h (10 mmol) and ethanol (75 mL) wasrefluxed for 1 h. The mixture was concentrated and the residue dissolvedin ethyl acetate. The solution was washed twice with water and thesolvent removed to yield the crude product, which was recrystallizedfrom hexane. GC/MS showed some remaining isocyanate so the solid wasdissolved in ethanol and refluxed again with approx. 0.1 gdiazobisbicyclooctane. FID/GC indicated a complete reaction and theethanol was removed and the title compound recovered. m.p. 109-110° C.

Example 110 N-[2-Chloro-6-(trimethylsilyl)phenyl]-N'-ethylurea

To a solution of the compound of Example h (4 mmol) in 50 mL toluene wasadded 70% ethyl amine (4 mL). The solution was stirred for 0.5 h andthen stood overnight. Ethyl acetate was added and the mixture was washedwith water. The organic layer was concentrated to a semisolid, which wastriturated with hexane. The title compound was collected by filtrationas 0.9 g of crystals, an 83% yield. m.p. 161-163° C.

Example 111 [2-Chloro-6-(trimethylsilyl)phenyl]carbamic acid,1,1-dimethylethyl ester

o-Chlorophenyl isocyanate (0.16 mol) was dissolved in toluene (250 mL),and tert-butanol (12.9 g, 0.174 mol) was added. After refluxingovernight, the cooled solution was filtered. The solvent was removedfrom the filtrate and (2-chlorophenyl)carbamic acid, 1,1-dimethylethylester was recovered.

This compound was combined with t-BuLi in THF at -71° C. using theprocedures described above and then reacted with TMSCl. The titlecompound was recovered as 1.3 g of crystals. m.p. 90-91° C.

Examples 112-114 Compound 112:(Z)-2-Chloro-N-1-propenyl-6-(trimethylsilyl)benzamide Compound 113:(E)-2-Chloro-N-1-propenyl-6-(trimethylsilyl)benzamide Compound 114: A50:50 mixture of Compounds 112 and 113

The compound of Example 106 (17 mmol) and of Wilkinson's catalyst[tris(triphenylphosphine)rhodium(I) chloride] (80 mg) were dissolved in100 mL toluene and refluxed for four days. The mixture was filteredthrough silica gel, which was washed with ethyl acetate and combinedwith the filtrate. The solvent was removed and the mixture was resolvedby RC with 1:9 ethyl acetate/hexane to yield two fractions havingdifferent tlc spots. The first fraction was concentrated to yield asolid which was recrystallized from hexane to yield 1.9 g of Compound114 (m.p. 100.0-105.0). This solid (0.25 g) was purified by RC withhexane as a solvent to yield Compound 112 (m.p. 140.0-141.0° C.) andCompound 113 (m.p. 101.0-102.0° C.) as pure isomers.

Example 115 2-Chloro-N-ethyl-6-(trimethylstannyl)benzamide

1.3M s-BuLi in cyclohexane (25.8 mL, 33.5 mmol) was added dropwise to a-78° C. cooled solution of the compound of example f (2.80 g, 15.3 mmol)and TMEDA (3.55 g, 30.6 mmol) in THF (100 mL). After stirring theresulting reaction mixture at -78° C. for 15 min, hexamethylditin (5.0g, 15.3 mmol) was added. The reaction was warmed to -60° C., and thenpartitioned between ether and water. The ether was dried (MgSO₄),concentrated, and purified by silica gel chromatography, eluting with1:4 ethyl acetate/hexanes, to afford 4.10 g of the title compound as awhite solid, a 77% yield. m.p. 78-80° C.

Example 116 2-Chloro-N-ethyl-6-(9-phenanthrenyl)benzamide

The title compound was prepared by treatment of 9-bromophenanthrene(0.94 g, 3.65 mmol) according to General Method D. It was obtained as0.55 g of a white solid, a 56% yield. m.p. 189-191° C.

Example 117 N-Ethyl-2-fluoro-6-(trimethylsilyl)benzamide

2-Fluorobenzoyl chloride (2 g, 12.6 mmol) and 70% aq ethyl amine (1.78g, 27.7 mmol) were combined in CH₂ Cl₂ according to General Method E1,and kugelrohr distilled to give 1.85 g of N-ethyl-2-fluorobenzamide as acolorless oil, an 87% yield.

A solution of 1.3M s-BuLi in cyclohexane (20.3 mL, 26.4 mmol) was addedto an ether/liquid nitrogen cooled solution of N-ethyl-2-fluorobenzamide(2.00 g, 11.98 mmol) in THF (75 mL) and ether (75 mL), maintaining theinternal reaction temperature ≦95° C. The resulting mixture was stirredat this temperature for 30 min, then TMSCl (1.43 g, 13.2 mmol) was addedand the mixture warmed to -60° C. After 2 h, the reaction was pouredinto water (200 mL). The organic layer was dried (MgSO₄), concentrated,and purified by silica gel chromatography, eluted with 3:7 ethylacetate/hexanes, to afford 0.45 g of the title compound as a whitesolid, a 16% yield. m.p. 86-87° C.

Example 118 1-[3-Fluoro-2,6-bis(trimethylsilyl)benzoyl]pyrrolidine

3-Fluorobenzoyl chloride was reacted with pyrrolidine using GeneralMethod E1 or E2 to produce N-(3-fluorobenzoyl)pyrrolidine.

A solution of 1.3M s-BuLi in cyclohexane (23.91 mL, 31.1 mmol) was addedto an ether/liquid N₂ cooled (-90° C.) solution of TMEDA (3.97 g, 34.2mmol) in THF (40 mL), followed by the addition of a solution ofN-(3-fluorobenzoyl)pyrrolidine (5.0 g, 25.9 mmol) in a minimum volume ofTHF. The resulting reaction mixture was stirred at -90° C. for 15 min,then TMSCl (6.75 g, 62.2 mmol) was added in a single portion. Thereaction was warmed to RT, quenched with dilute aq citric acid, then wasextracted with ether (3×). The combined ether extracts were dried(MgSO₄), concentrated, and purified by HPLC with 3:7 EtOAc/hexanes toafford 0.45 g of the title compound as an oil, a 45% yield, whichsolidified on standing to a white solid. m.p. 97-100° C.

Example 119 2-Chloro-N,N-diethyl-6-(trimethylgermyl)benzamide

A solution of 1.3M s-BuLi in cyclohexane (21.8 mL, 28.3 mmol) was addeddropwise to a dry ice/acetone cooled solution of the compound of examplee (4.6 g, 21.7 mmol) in THF (60 mL), maintaining the internal reactiontemperature ≦-65° C. This mixture was stirred at -78° C. for 45 min,then was quenched by the dropwise addition of a solution oftrimethylchlorogermane (5.0 g, 32.6 mmol) in THF (30 mL), againmaintaining the internal reaction temperature ≦-65° C. The reaction waswarmed to 0° C., diluted with ether, and extracted with 10% HCl (2×)followed with sat aq NaHCO₃. The ether was dried (MgSO₄), concentrated,and purified by HPLC with 6% EtOAc in hexanes to afford 3.2 g of thetitle compound as a white solid, a 45% yield. m.p. 47-48° C.

Example 120 2-Bromo-N-(2-methylphenyl)-6-(trimethylsilyl)benzamide

The compound of Example c (0.0035 mol, 0.95 g), 15 mL thionyl chloride,and 1 drop of DMF were combined and stirred at RT overnight. Toluene (50mL) was added and the mixture concentrated to dryness. This process wasrepeated three times, and the residue dissolved in CH₂ Cl₂ (50 mL).2-Methylaniline (0.0035 mol, 0.37 g) and triethylamine (0.0035 mol, 0.39g) were added and the mixture was stirred at RT overnight. The mixturewas washed with 10% HCl and twice with water; dried (MgSO₄) andconcentrated. The title compound was recrystallized from hexanes as atan solid in 71% yield. m.p. 113-115° C.

Example 121 N-(2-Methylphenyl)-2-(trimethylsilyl)benzamide

The compound of Example 120 (0.0021 mol, 0.75 g) and 50 mL THF werecooled to -78° C. in a nitrogen atmosphere with magnetic stirring. 1.3Ms-BuLi (0.0026 mol, 2 mL) in cyclohexane was added dropwise. Afterstirring for 30 min, 25 mL of 25% citric acid were added. The mixturewas then extracted three times with ethyl acetate, the extracts combinedand washed with brine and twice with water, dried (MgSO₄) andconcentrated. The title compound was recrystallized as a white solidfrom ethyl acetate/hexanes in 54% yield. m.p. 117-119° C.

Example 122 2-Chloro-N-ethyl-6-(2-naphthalenyl)benzamide

The title compound was prepared by treatment of 2-bromonaphthalene (0.76g, 3.65 mmol) according to General Method D. It was obtained as 0.68 gof a white solid, a 60% yield. m.p. 182-184° C.

Example 123 N-Ethyl-2-fluoro-6-(1-methylcyclopentyl)benzamide

To lithium sand (0.44 g, 63.0 mmol) in THF (100 mL) at 0° C. under argonwas added 4,4'-di-tert-butylbiphenyl (13.27 g, 51.0 mmol) and theresulting mixture was stirred at 0° C. overnight. The mixture was thencooled to -78° C. and 1-chloro-1-methylcyclopentane (3.0 g, 25.3 mmol)in THF (25 mL) was added. [1-Chloro-1-methylcyclopentane, a clear oilwith b.p. 87-88° C./15T was obtained by the chlorination of1-methylcyclopentanol with HCl gas.] This mixture was stirred for 15 minand the compound of Example g (5.34 g, 25.3 mmol) was added. Theresulting solution was stirred at -78° C. for 1 h before being pouredinto water (250 mL). The aq layer was extracted three times with ether,and the combined extracts were dried (MgSO₄) and concentrated to yield2-[2-fluoro-6-(1-methyl-cyclopentyl)phenyl]-4,5-dihydro-4,4-dimethyloxazole,as a clear oil in 40% yield. This oxazoline was carried through Steps1-4 of Example 90. The resulting final product was recrystallized fromether/hexanes and obtained as a white solid. m.p. 116-117° C.

Example 124 N-Ethyl-3-(trimethylsilyl)-4-pyridinecarboxamide

A solution of 4-pyridinecarboxylic acid (20 g, 0.16 mol) in 60 mLthionyl chloride was stirred at RT for 24 h. After that, excess thionylchloride was removed in vacuo. The solid residue was added in portionsto a mixture of 60 g of 70% ethylamine in water and 200 mL CH₂ Cl₂ at-5° C. and then stirred at RT for 18 h. Water was added. The organicsolution was separated, washed with water, brine, dried and concentratedto give 9.5 g of the crude N-ethyl-4-pyridinecarboxamide.

A solution of N-ethyl-4-pyridinecarboxamide in THF was metallated withlithium diisopropylamide (prepared from diisopropyl amine and 2.5Mn-BuLi in hexane according to the method of Example 250) and quenchedwith TMSCl as in step c of Example 248. The title compound was purifiedby flash chromatography first with 20%, and then 70% ethylacetate-hexane as eluent and recovered as a white solid. m.p. 93-95° C.

Example 1252-Chloro-N-ethyl-N-(2-furylmethyl)-6-(trimethylsilyl)benzamide

A 1.0M THF solution of sodium bis(trimethylsilyl)amide (7.7 mL, 7.7mmol) was added dropwise to a solution of the compound of Example 32(2.15 g, 7.0 mmol) in THF (30 mL). After stirring 1 h, a solution ofethyl iodide (1.31 g, 8.4 mmol) in THF (15 mL) was added. The resultingreaction was stirred overnight at RT, then was partitioned between ethylacetate and dilute aq citric acid. The organic solution was washed twicewith sat aq NaHCO₃ and then twice with brine, then was dried (MgSO₄) andconcentrated to afford 1.8 g of the title compound as an amber oil, a77% yield.

Example 126 2-Chloro-N,N-bis(1-methylethyl)-6-(trimethylsilyl)benzamide

The compound of Example b (2.47 g, 10 mmol), diisopropyl amine (2.23 g,22 mmol), and toluene (25 mL) were combined according to General MethodE2. The crude product was recrystallized from ethanol/water to afford1.75 g of the title compound as a white solid, a 58% yield. m.p.96-97.5° C.

Example 127N-Ethyl-N-(methoxymethyl)-2-methyl-6-(trimethylsilyl)benzamide

The compound of Example 50 (1.33 g, 5.0 mmol) and MeI (2.8 g, 20 mmol)were combined according to General Method B. The resulting reaction waspartitioned between ethyl acetate and sat aq NaHCO₃. The organic phasewas washed with brine, dried (MgSO₄), and concentrated to afford aquantitative yield of the title compound as an oil.

Example 1282-Chloro-N-(2-ethoxyethyl)-N-ethyl-6-(trimethylsilyl)benzamide

The compound of Example b (4.94 g, 20 mmol), 2-ethoxyethyl amine (3.92g, 44 mmol), and toluene (35 mL) were combined according to GeneralMethod E1. The crude product was recrystallized from aq ethanol toafford 3.97 g of N-(2-ethoxyethyl)-2-chloro-6-(trimethylsilyl)benzamideas white solid, a 66% yield. m.p. 71-73° C.

A 1M THF solution of sodium bis(trimethylsilyl)amide (7.7 mL, 7.7 mmol)was added dropwise over 5 min to a solution ofN-(2-ethoxyethyl)-2-chloro-6-(trimethylsilyl)benzamide (2.1 g, 7 mmol)in THF (30 mL). The resulting mixture was stirred for 1 h at RT, then asolution of ethyl iodide (1.31 g, 8.4 mmol) in THF (15 mL) was addedwith a mild exotherm. The resulting reaction mixture was stirredovernight, then was partitioned between ethyl acetate and dilute aqcitric acid. The ethyl acetate phase was washed with sat aq NaHCO₃followed with brine, then was dried (MgSO₄) and concentrated to afford1.9 g of the title compound as an amber oil, an 83% yield.

Examples 129-134 and 144-163

The following examples were prepared by reaction of the compound ofExample b and the appropriate amine by General Method E1. Melting pointsare reported in °C.

    ______________________________________                                        Ex. No.   Compound Name    M.P.                                               ______________________________________                                        129       2-Chloro-N-cyclohexyl-6-                                                                       198.5-200.5                                                       (trimethylsilyl)benzamide                                        130         N-[2-Chloro-6-    --                                                           (trimethylsilyl)benzoyl]-2,6-                                                 dimethylmorpholine                                               131         N-[2-Chloro-6-                  187.5-190                                      (trimethylsilyl)benzoyl]-2,6-                                                 dimethylpiperidine                                               132         N-[2-Chloro-6-                    110-111.5                                    (trimethylsilyl)benzoyl]-                                                     morpholine                                                       133         N-[2-Chloro-6-                    76-77.5                                      (trimethylsilyl)benzoyl]-4-                                                   methylpiperazine                                                 134         N-[2-Chloro-6-                    111-113                                      (trimethylsilyl)benzoyl]-                                                     piperidine                                                     ______________________________________                                    

Examples 135-142

The following examples were prepared by reaction of the compound ofExample b and the appropriate amine in dioxane in the presence of aslight molar excess of triethyl amine using the amination methodsdescribed above. The melting points are reported in °C.

    ______________________________________                                        Ex. No.  Compound Name      M.P.                                              ______________________________________                                        135      2-Chloro-N-(2-     84-88                                                            pyridinylmethyl)-6-                                                           (trimethylsilyl)benzamide                                        136         2-Chloro-N-[(4-                    100-103                                     methoxyphenyl)methyl]-6-                                                      (trimethylsilyl)benzamide                                        137         2-Chloro-N-[(4-nitrophenyl)-       131-135                                     methyl)-6-(trimethylsilyl)-                                                   benzamide                                                        138         2-Chloro-N-(2-thienylmethyl)-        120-122                                   6-(trimethylsilyl)benzamide                                      139         2-Chloro-N-[(3-                    85-87                                       methoxyphenyl)methyl]-6-                                                      (trimethylsilyl)benzamide                                        140         2-Chloro-N-[(3,4,5-                128-130                                     trimethoxyphenyl)methyl)-6-                                                   (trimethylsilyl)benzamide                                        141        2-Chloro-N-[(3-nitrophenyl)-        121-122                                    methyl]-6-(trimethylsilyl)-                                                   benzamide                                                         142        2-Chloro-N-(cyanoxnethyl)-6-          145-147                                  (trimethylsilyl)benzamide                                         144        N-(1,3-benzodioxol-5-                 138-140                                  ylmethyl)-2-chloro-6-                                                         (trimethylsilyl)benzamide                                         145        2-Chloro-N-(4-                        122-125                                  pyridinylmethyl)-6-                                                           (trimethylsilyl)benzamide                                         146        2-Chloro-N-(2-methoxyethyl)-6-        75-77                                    (trimethylsilyl)benzamide                                         147        2-Chloro-N-(2-methyl-2-               118-121                                  propenyl)-6-                                                                  (trimethylsilyl)benzamide                                         148        1-[2-Chloro-6-                      109-111                                    (trimethylsilyl)benzoyl)-                                                     1,2,3,6-(tetrahydro)pyridine                                      149        1-[2-Chloro-6-                      75-77                                      (trimethylsilyl)benzoyl)-2,5-                                                 dihydro-2,5-dimethyl-1H-                                                      pyrrole                                                           150        2-Chloro-N-                           99-101                                   (cyclopropylmethyl)-6-                                                        (trimethylsilyl)benzamide                                         151        2-Chloro-N-(1-methylpropyl)-6-        148-149                                  (trimethylsilyl)benzamide,                                                    (r)-                                                              152        2-Chloro-N-(1-methylpropyl)-6-        149-150                                  (trimethylsilyl)benzamide,                                                    (s)-                                                              153        N-(2-Bromoethyl)-2-chloro-6-          101-103                                  (trimethylsilyl)benzamide                                         154        2-Chloro-N-(2-hydroxy-1-              108-111                                  methylethyl)-6-                                                               (trimethylsilyl)benzamide                                         155        2-Chloro-N-(2-fluoroethyl)-6-         103-105                                  (trimethylsilyl)benzamide                                         156        2-Chloro-N-[2-(1-                   92-94                                      methylethyl)phenyl]-6-                                                        (trimethylsilyl)benzamide                                         157        2-Chloro-N-(2-ethoxyphenyl)-6-        73-76                                    (trimethylsilyl)benzamide                                         158        2-Chloro-N-(2-                        110-113                                  cyclopentylphenyl)-6-                                                         (trimethylsilyl)benzamide                                         159        2-Chloro-N-(2-methoxyphenyl)-         75-76                                    6-(trimethylsilyl)benzamide                                       160        2-Chloro-N-(2-nitrophenyl)-6-         88-90                                    (trimethylsilyl)benzamide                                         161        2-Chloro-N-(1-phenylethyl)-6-         129-132                                  (trimethylsilyl)benzamide                                         162        2-Chloro-N-(2-methylpropyl)-6-        132-133                                  (trimethylsilyl)benzamide                                         163        2-Chloro-N-cyclobutyl-6-              145-146                                  (trimethylsilyl)benzamide                                       ______________________________________                                    

Example 143N-Ethyl-N-(hydroxymethyl)-2-methyl-6-(trimethylsilyl)benzamide

The compound of Example 127 (0.80 g, 2.9 mmol) was refluxed in a mixtureof acetonitrile (20 mL) and 2N HCl 20 mL). Within 2 h the reaction wascomplete by GLC, and was cooled and partitioned between ether and water.The ether phase was concentrated and purified by RC with 1:4 ethylacetate/hexanes, then recrystallized from hexanes to give 160 mg of thetitle compound as a solid, a 21% yield.

Example 1642-Chloro-N-methyl-N-(1-methylethyl)-6-(trimethylsilyl)benzamide

Thionyl chloride (1.5 g, 12 mmol) was dissolved in 50 mL CH₂ Cl₂ and thecompound of Example 154 (dissolved in 50 mL CH₂ Cl₂) was dropped inslowly. A drop of DMF was added and the mixture stirred overnight. Waterwas added and the mixture extracted with ethyl acetate to yield a solidwhich was recrystallized from 5% ethyl acetate/hexane.2-Chloro-N-(2-chloro-1-methylethyl)-6-(trimethylsilyl)benzamide wasobtained (2.2 g, 7.3 mmol, 73% yield). m.p. 150-151° C.

This compound (1.5 g, 5.0 mmol) was dissolved in 50 mL THF and 5.5 mL 1M (in THF) potassium t-butoxide (5.5 mmol) was added. After standing 4hrs, water was added the mixture extracted with ethyl acetate. Removalof solvent yielded an oil identified as2-[2-chloro-6-(trimethylsilyl)phenyl]-4,5-dihydro-4-methyl-oxazole.

This compound (2.67 g, 10 mmol) and trimethyloxonium fluoroborate (1.5g, 10 mmol) were dissolved in CH₂ Cl₂ and allowed to stir 18 days. Etherwas added to the mixture and the precipitate collected. The product,identified as2-[2-chloro-6-(trimethylsilyl)phenyl]-4,5-dihydro-3,4-dimethyl-oxazoliumtetrafluoroborate, was recrystallized by redissolving it in CH₂ Cl₂ andadding ether to the cloud point. m.p. 155-157° C.

This compound (1.9 g, 5.1 mmol) and sodium cyanoborohydride (0.32 g)were added to methanol and stirred overnight. The mixture was filteredand water added to the mother liquor. Extraction with ethyl acetateyielded an oil upon solvent removal. The oil was dissolved in 50% ethylacetate/hexane and filtered through silica gel. Removal of the solventyielded an oil which was purified by RC (20% ethyl acetate/hexane).

Example 1652-Chloro-N-[(2-propenylamino)carbonyl]-6-(trimethylsilyl)benzamide

Silver cyanate (3.0 g, 20 mmol) which had been dried overnight at 140°was added to dry toluene followed by 2-chloro-6-trimethylsilylbenzoylchloride (Example b) (2.46 g, 10 mmol). After refluxing 4 hrs, allylamine (0.6 g, 10 mmol) is added and the mixture refluxed overnight.After filtration through silica gel to remove silver salts, the solventwas removed to yield an oil. Trituration with hexane produced 0.7 g ofthe title compound as a solid. m.p. 68-71° C.

Example 166 2-Chloro-N,N-diethyl-6-[(trimethylsilyl)methyl]benzamide

The compound from example e (1.0 eq) and MeI (3.0 eq) were combinedaccording to Method A. The crude product was purified by HPLC with 1:4EtOAc/hexanes to give 5.2 g of N,N-diethyl 2-chloro-6-methylbenzamide asa yellow solid, a 92% yield. m.p. 48°-49° C.

This compound (1.0 eq) and TMSCl (2.0 eq) were combined according toMethod A, and purified by HPLC with 1:9 EtOAc/hexanes to give 2.1 g ofthe title compound as a clear oil, a 59% yield.

Example 1672-Chloro-N-hydroxy-N-(1-methylethyl)-6-(trimethylsilyl)benzamide

The title compound was prepared by reaction of the compound of Example band the i-propylhydroxylamine hydrochloride in dioxane in the presenceof two equivalents of triethylamine using the amination methodsdescribed above. m.p. 175-179° C.

Example 1682-Chloro-N-hydroxy-N-(1-methylethyl)-6-(trimethylsilyl)benzamide, compd.with iron hydroxide (1:1)

The compound of Example 167 (0.47 g, 1.6 mmol) was added to 40 mL 0.5 Msodium acetate solution. Acetone was added to this suspension to a totalof 80 mL. Slight warming yielded a homogeneous solution. Ferric chloride(0.44 g, 1.6 mmol), dissolved in 10 mL water, was added. A precipitateforms which seems to be colloidal in nature. Stripping of the acetoneyielded a precipitate which could be easily filtered off and dried undervacuum overnight to yield 0.50 g of the title compound. m.p. 260° C.

Example 169 2-Chloro-N-ethyl-6-(trimethylsilyl)benzenecarboximidothioicacid, ethyl ester

A solution of 9.66 g (36 mmol) of the compound of Example 76 and 40 mLtrimethyloxonium tetrafluoroborate (1.0 M, 40 mmol) was allowed to standovernight at RT. The mixture was stripped to 40 mL and 300 mL etheradded to precipitate the product, which was identified as 9.5 g ofN-[[2-chloro-6-(trimethylsilyl)phenyl](ethylthio)methylene]ethanamine(1:1) compound with tetrafluoroborate hydrate. m.p. 160-161° C.

To 3.87 g (10 mmol) of this compound in 100 mL CH₂ Cl₂ was added 1.5 g(15 mmol) of triethyl amine. After standing a few minutes, the mixturewas extracted with 100 mL water and the solvent removed to yield an oil.Purification was accomplished by RC (10% ethyl acetate/hexane) to yield2.5 g of pure oil.

Example 170N-(1H-Benzotriazol-1-ylphenylmethyl)-2-chloro-6-(trimethylsilyl)benzamide

A mixture of 2-chloro-6-trimethylsilylbenzamide (2.27 g, 10 mmol), whichmay be readily prepared by the reaction of the compound of Example b andammonium hydroxide, benzaldehyde (1.1 g, 10 mmol), and benzotriazole(1.2 g, 10 mmol) was refluxed 5 days in toluene utilizing a Dean-Starktrap to remove water. The solvent was removed to yield an oil whichcrystallizes. Recrystallization from ethyl acetate yielded 0.5 g of thetitle compound. m.p. 184-186° C.

Example 1712-Chloro-N-(2-chloro-1-methylethyl)-6-(trimethylsilyl)benzamide

This compound was prepared in the first step of Example 164. m.p.150-151° C.

Example 172 2-Chloro-N-ethyl-N-(methylthio)-6-(trimethylsilyl)benzamide

The compound of Example 45 (2.55 g, 10 mmol) was dissolved in 50 mL dryTHF, and N-thiomethyl phthalimide (1.93 g, 10 mmol) was added followedby 12 mL of 1 M LiN(TMS)₂ (in THF) (12 mmol). All operations werecarried out under nitrogen. After stirring at RT overnight gc/msanalysis suggested a mixture of the desired product and phthalimide.Water was added the mixture extracted with ethyl acetate. Removal of thesolvent yielded a semisolid. Addition of 15% ethyl acetate/hexanegenerated a solid which was filtered off and discarded. The motherliquor was purified by RC (15% ethyl acetate/hexane) to yield 0.2 g.

Example 1732-Chloro-N-(isopropylaminocarbonyl)-6-(trimethylsilyl)benzamide

To 0.1 m of 2-chloro-6-(trimethylsilyl)benzamide, prepared by thereaction of the compound of Example b and ammonium hydroxide, inethylene dichloride was added 1.2 eq oxalyl chloride and 2 drops of DMF.After refluxing overnight, the solvent is stripped off and the resultingoil Kugelrohred at 0.2 mm (87-92°) to yield 21 g (84%) of isocyanate. Itis important to exclude moisture from the reaction; otherwise theprimary amide is formed.

2-Chloro-6-trimethylsilylbenzoyl isocyanate (1.3 g, 5 mmol) wasdissolved in 40 mL toluene and isopropyl amine (1 g) added over a periodof 30 seconds. After stirring 30 min, the solvent was removed to yieldan oil. The oil was dissolved in hexane and cooled in dry ice to yield1.2 g of crystals of the title compound. m.p. 113-116° C.

Example 174 2-Chloro-N-(methylthio)-6-(trimethylsilyl)benzamide

To 1.1 g of 2-chloro-6-(trimethylsilyl)benzamide, prepared from Exampleb and ammonium hydroxide, (5 mmol) in 50 mL THF was added 5.5 mL of 1 M(in THF) potassium t-butoxide (5.5 mmol) followed by 0.95 gN-thiomethylphthalimide (5 mmol). After standing overnight, gc/mssuggested close to a 50/50 mix of product to starting benzamide. Waterwas added and the mixture extracted with ethyl acetate. Removal of thesolvent yielded a semisolid. Trituration with 50 mL 15% ethylacetate/hexane yielded a solid which was filtered off and collected. Themother liquor was purified by RC (20% ethyl acetate/hexane). The firstband was collected and stripped to an oil which crystallized upontrituration with hexane and to yield 0.3 g of the title compound. m.p.92-94° C.

Example 1752,2,2-Trichloro-N-[2-chloro-6-(trimethylsilyl)phenyl]acetamide

To a solution of 53.0 g (215 mmol) of the compound of Example b in 500mL acetone was added 15.3 g (235 mmol) sodium azide and 50 mL water. Themixture was stirred for 15 min and gas evolution began to subside. Themixture was then heated to reflux for 22 h. Acetone was then removed invacuo and the residue was partitioned between ether and water. Theorganic layer was washed with brine, dried (MgSO₄) and was filteredthrough silica gel. The filtrate was evaporated in vacuo to yield 42.8 g(100%) of a colorless oil, identified as2-(trimethylsilyl)-6-chloroaniline.

To a solution of 2.0 g (10.0 mmol) of this compound and 0.8 g (10.1mmol) pyridine in 30 mL dry THF was added 1.82 g (10.0 mmol)trichloroacetyl chloride. The mixture was stirred at ambient for 4 h andwas then partitioned between ether and water. The organic layer waswashed with brine, dried (MgSO₄), and was filtered through silica gel.The filtrate was evaporated in vacuo and the residue was triturated inether/hexane to yield the title compound as 2.9 g of white crystals.m.p. 188.5-189° C.

Example 176 2-Bromo-N-ethyl-6-(trimethylsilyl)benzamide

The compound of Example d (38.19 g, 0.13 mol) was reacted with 70%aqueous ethylamine (53 mL) according to General Method E1 andrecrystallized from methylcyclohexane to afford the title compound aslight tan crystals in 92% yield. m.p. 121-122° C.

Example 177 2-Chloro-N-ethyl-4-(trimethylsilyl)-3-thiophenecarboxamide

A mixture of 3-thiophenecarboxylic acid (20 g, 178 mmol), thionylchloride (30 mL), and DMF (5 drops) was stirred overnight, then wasconcentrated under vacuum and stripped several times from toluene toremove all traces of excess thionyl chloride. Pyridine (31.64 g, 400mmol) was added dropwise to a mixture of this acid chloride andethylamine hydrochloride in toluene (5 mL) and CH₂ Cl₂ (50 mL). Afterstirring for 1 h, the reaction was washed with 10% aq HCl followed withwater, then was dried (MgSO₄), concentrated, and crystallized from ethylacetate/hexanes to give 14.9 g of N-ethyl-3-thiophenecarboxamide as atan solid, a 76% yield. m.p. 115°-117° C.

A solution of 1.3M s-BuLi in cyclohexane (44 mL, 57.2 mmol) was addeddropwise to a -78° C. cooled solution of N-ethyl-3-thiophenecarboxamide(4.04 g, 26 mmol) and TMEDA (6.65 g, 57.2 mmol) in THF (100 mL). Afterstirring for 30 min at -78° C., a solution of hexachloroethane (13.54 g,57.2 mmol) in THF (20 mL) was added dropwise. The resulting reactionmixture was warmed to RT over 1 h, quenched with dilute aq citric acid,and extracted with EtOAc (3×). The combined organic extracts were dried(MgSO₄), concentrated, and purified by HPLC with 3:7 EtOAc/hexanes togive 2.8 g of N-ethyl-2-chloro-3-thiophenecarboxamide as a yellow oil, a57% yield.

A solution of 1.3M s-BuLi in cyclohexane (16.15 mL, 21 mmol) was addeddropwise to an ether/liquid N₂ cooled (-100° C.) solution ofN-ethyl-2-chloro-3-thiophenecarboxamide (1.90 g, 10 mmol) and TMEDA(3.17 mL, 21 mmol) in THF (100 mL). After stirring for 30 min at -100°C., TMSCl (2.28 g, 21 mmol) was added in a single portion. The resultingreaction mixture was warmed to -25° C. over 1 h, quenched with dilute aqcitric acid, and extracted with EtOAc (3×). The combined organicextracts were dried (MgSO₄), concentrated, and purified by HPLC with3:17 EtOAc/hexanes to afford 0.3 g of the title compound as a whitesolid, an 11% yield. m.p. 46-48° C.

Example 178 N-Ethyl-2-(trimethylsilyl)-1H-pyrrole-1-carboxamide

60% NaH in mineral oil (1.8 g, 45 mmol) was added to an ice-water cooledsolution of pyrrole (2.01 g, 30 mmol) in THF (100 mL) over a 15 minperiod. After 1 h, the reaction mixture was cooled to -78° C. and ethylisocyanate (1.78 g, 25 mmol) was added. This mixture was allowed to warmto RT and stirred overnight, then was partitioned between ether anddilute aq citric acid. The ether phase was dried (MgSO₄), filteredthrough silica gel, concentrated, and recrystallized from ether/hexanesto give a 39% yield of pyrrole-1-(N-ethyl carboxamide).

1.3M s-BuLi in cyclohexane (18.5 mL, 24 mmol) was added dropwise to adry-ice/acetone cooled solution of pyrrole-1-(N-ethyl carboxamide) (1.38g, 10 mmol) and 2,2,6,6-tetramethylpiperidine (1.55 g, 11 mmol) in THF(50 mL). After stirring for 30 min at -78° C., TMSCl (1.63 g, 15 mmol)was added in a single portion. The reaction was allowed to slowly warmto Rt over 30 min, then was quenched with dilute aq citric acid andextracted with ethyl acetate (3×). The combined organic solutions weredried (MgSO₄), concentrated, and crystallized from ether/hexanes to give0.8 g of the title compound as a white solid, a 38% yield. m.p.100°-103° C.

Example 179 2-Chloro-6-(dimethyl-2-propenylsilyl)-N-ethylbenzamide

A solution of 1.3M s-BuLi in cyclohexane (10.5 mL, 13.6 mmol) was addeddropwise to a dry-ice/acetone cooled solution of TMEDA (1.0 mL, 6.5mmol) in THF (10 mL), followed by the dropwise addition of a solution ofthe compound of example f (1.0 g, 5.45 mmol) in THF (10 mL). Thereaction mixture was stirred at -78° C. for 30 min, thenallyldimethylchlorosilane (10.9 mmol) was added and the mixture wasstirred for 2.5 h at -78° C. The resulting reaction was warmed to -30°C., quenched with dilute aq citric acid, diluted with water, andextracted with EtOAc (2×). The combined organic extracts were dried(MgSO₄), concentrated, and purified by HPLC with 1:19 EtOAc/cyclohexaneto give the desired compound as a white solid. m.p. 61-63° C.

Example 180 2-Chloro-6-[dimethyl(1-methylethyl)silyl]-N-ethylbenzamide

The title compound was prepared as in Example 179 fromisopropyldimethylchlorosilane in 62% yield. m.p. 98°-100° C.

Example 181 2-Chloro-6-(cyclohexyldimethylsilyl)-N-ethylbenzamide

The title compound was prepared as in Example 179 fromcyclohexyldimethylchlorosilane in 71% yield. m.p. 111-113° C.

Example 182 2-Chloro-6-(dimethyloctylsilyl)-N-ethylbenzamide

The title compound was prepared as in Example 179 fromoctyldimethylchlorosilane in 78% yield. m.p. 62-63° C.

Example 1832-(Bicyclo[2.2.1]Hept-2-yldimethylsilyl)-6-chloro-N-ethylbenzamide

The title compound was prepared as in Example 179 from 2-bicycloheptyldimethylchlorosilane in 58% yield. m.p. 124-125° C.

Example 184 2-Chloro-6-(dimethylphenylsilyl)-N-ethylbenzamide

The title compound was prepared as in Example 179 fromphenyldimethylchlorosilane in 44% yield. m.p. 89-91° C.

Example 1852-Chloro-6-[(1,1-dimethylethyl)dimethylsilyl]-N-ethylbenzamide

The title compound was prepared as in Example 179 fromtert-butyldimethylchlorosilane in 28% yield. m.p. 140-142° C.

Example 1862-(1,1-Dimethylethyl)-N-ethyl-N-(1-methoxy-2,2-dimethylpropyl)benzamide

A mixture of 2-tert-butylbenzoic acid (15.7 g, 88.2 mmol) and thionylchloride (19.3 mL, 265 mmol) was stirred at RT for 1 day, then wasconcentrated and stripped from toluene (2×) under vacuum. The compoundfrom example k (19.94 g, 176.5 mmol) was added to a solution of thiscrude 2-tert-butylbenzoyl chloride in toluene (90 mL), and the mixturewas heated at 100° C. for 3 h, then was stirred at room temperatureovernight. The resulting mixture was cooled with an ice-water bath, andEt₃ N (13.4 g, 132.4 mmol) was added, followed by the dropwise additionof methanol (5.65 g, 176.6 mmol). The resulting reaction mixture wasstirred at RT and monitored to completion by GLC, then was partitionedbetween ether and sat aq NaHCO₃. The ether extract was dried (MgSO₄),concentrated, and purified by flash chromatography with 1:9EtOAc/hexanes to afford 20.8 g of the title compound as a pale yellowoil, a 77% yield.

Example 187N-Ethyl-N-(1-methoxy-2,2-dimethylpropyl)-2-(trimethylsilyl)benzamide

A solution of the compound of Example k (30 g, 265 mmol) in CH₂ Cl₂ (60mL) was added to an ice-water cooled solution of benzoyl chloride (36 g,256 mmol) in CH₂ Cl₂ (180 mL). The cooling bath was then removed and amild exotherm occurred. After 1 h the reaction was cooled with anice-water bath, then Et₃ N (4.44 g, 43.9 mmol) was added in a singleportion, followed by the dropwise addition of methanol (2.55 g, 79.7mmol) with formation of a precipitate. The resulting reaction wasstirred at RT for 30 min, then was partitioned between ether and sat aqNaHCO₃. The ether phase was dried (MgSO₄),concentrated, and kugelrohrdistilled under vacuum to afford 61.23 g of pureN-ethyl-N-(1-methoxy-2,2-dimethylpropyl)benzamide as an oil, a 96%yield.

A solution of 1.3M s-BuLi in cyclohexane (140.6 mL, 182.8 mmol) wasadded dropwise to a dry-ice/acetone cooled solution ofN-ethyl-N-(1-methoxy-2,2-dimethylpropyl)benzamide (35 g, 140.6 mmol) andTMEDA (25.44 mL, 168.6 mmol) in THF (280 mL), maintaining the internalreaction temperature ≦-60° C. The yellow solution was stirred at -78° C.for 1 h, then was cannulated into a dry-ice/acetone cooled solution ofTMSCl (26.72 mL, 210.6 mmol) in THF (140 mL) at a rate which maintainedthe internal reaction temperature ≦-55° C. The resulting mixture waswarmed to 0° C. and partitioned between ether and sat aq NaHCO₃. Theether solution was dried (MgSO₄), concentrated, and kugelrohr distilledunder vacuum to give 44.8 g of the title compound as a pale yellowsolid, a 99% yield. m.p. 76-78° C.

Example 188 2-[(1,1-Dimethylethyl)methylamino]-N-ethylbenzamide

70% Perchloric acid (22.5 g, 157 mmol) was added dropwise to anice-water cooled solution of anthranil (9.53 g, 80 mmol) and tertiarybutanol (5.93 g, 80 mmol). The resulting mixture was stirred at Rtovernight, then was diluted with ether to form a slurry. The solid wascollected by filtration and dried under vacuum to afford 16.0 g ofN-tert butyl anthranilium perchlorate as a white solid.

N-tert butyl anthranilium perchlorate (15.6 g, 56.6 mmol) was added inportions to a solution of triethylamine (17.2 g, 170 mmol) in CH₂ Cl₂(150 mL). The mixture was stirred at Rt for 1 h, then was concentratedto a small volume, triturated with ether, and filtered to remove thesalts. The filtrate was concentrated and vacuum distilled to give 1.8 gof the N-tert butyl b-lactam as a yellow oil. b.p. 89°-90° C. at 0.2Torr.

This N-tert butyl b-lactam 0.52 g, 3 mmol) was added to a solution of70% aq EtNH₂ (0.58 g, 9 mmol) and CH₂ Cl₂ (50 mL). After stirring for 3dat RT the mixture was concentrated and crystallized from hexanes toafford 0.61 g of N-ethyl 2-(N-tert butylamino)benzamide as a whitesolid. m.p. 37°-40° C.

A mixture of this material, potassium carbonate (0.4 g, 2.86 mmol), andmethyl iodide (0.45 g, 3.15 mmol) in DMF (10 mL) was stirred at RTovernight, then was partitioned between ether and water. The ether wasdried (MgSO₄), concentrated, and purified by RC with 3:7 ethylacetate/hexanes, followed by recrystallization from hexanes to afford100 mg of the title compound as a white solid. m.p. 45°-48° C.

Example 1892-Chloro-6-[(1,1-dimethylethyl)methylamino]-N-ethyl-N-methylbenzamide

A solution of the N-tert-butyl b-lactam (1.1 g, 6.3 mmol) described inthe preparation of Example 188, and N-ethyl-N-methylamine (1.2 g, 20.8mmol) in CH₂ Cl₂ (50 mL) was stirred at RT overnight. The solvent wasevaporated and the residue purified by RC with EtOAc/cyclohexane to give1.277 g of N-ethyl-N-methyl 2-(N-tert-butylamino)benzamide as an orangeoil, an 86% yield.

A mixture of N-ethyl-N-methyl 2-(N-tert-butylamino)benzamide (1.89 g,8.1 mmol), potassium carbonate (2.2 g, 15.9 mmol), and methyl iodide(2.3 g, 16.2 mmol) in DMF (40 mL) was heated overnight at 40° C., thenwas partitioned between EtOAc and water. The EtOAc was dried (MgSO₄),concentrated, and purified by HPLC with 1:4 ethyl acetate/cyclohexane toafford 1.923 g of N-ethyl-N-methyl2-(N-methyl-N-tert-butylamino)benzamide as a yellow oil, a 96% yield.

A solution of 1.3M s-BuLi in cyclohexane (3.7 mL, 4.8 mmol) was addeddropwise to a dry-ice/acetone cooled solution of TMEDA (0.7 mL, 4.8mmol) in THF (10 mL), followed by the dropwise addition of a solution ofN-ethyl-N-methyl 2-(N-methyl-N-tert-butylamino)benzamide (1.0 g, 4.0mmol) in THF (5 mL). The reaction mixture was briefly warmed to -30° C.,then cooled to -78° C. and stirred for 15 min. A solution ofhexachloroethane (2.8 g, 12.1 mmol) in THF (5 mL) was added. Thismixture was stirred for 1 h at -78° C., then was warmed to -30° C.,diluted with water, and extracted with EtOAc (2×). The combined organicextracts were dried (MgSO₄), concentrated, and purified by HPLC with 1:4EtOAc/cyclohexane to give 528 mg of the title compound as a yellow oil,a 46% yield.

Example 190 2-Chloro-6-[(1,1-dimethylethyl)methylamino]-N-ethylbenzamide

A solution of 1.3M s-BuLi in cyclohexane (5.7 mL, 7.5 mmol) was addeddropwise to a dry-ice/acetone cooled solution of TMEDA (0.5 mL, 3.6mmol) in THF (10 mL), followed by the dropwise addition of a solution ofthe compound of Example 188 (0.7 g, 3.0 mmol) in THF (5 mL). Thereaction mixture was stirred at -78° C. for 30 min, thenhexachloroethane (2.1 g, 9.0 mmol) in THF (5 mL) was added. This mixturewas stirred for 30 min at -78° C., then was warmed to -30° C., dilutedwith water, and extracted with EtOAc (2×). The combined organic extractswere dried (MgSO₄), concentrated, and purified by HPLC with 3:17EtOAc/cyclohexane to give 495 mg of the title compound as a yellowsolid, an 61% yield. m.p. 106°-108° C.

Example 191 N-Ethyl-2-[(1,1-dimethylethyl)methylamino]-6-methylbenzamide

A solution of 1.3M s-BuLi in cyclohexane (9.8 mL, 12.8 mmol) was addeddropwise to a dry-ice/acetone cooled solution of TMEDA (0.6 mL, 3.8mmol) in THF (10 mL), followed by the dropwise addition of a solution ofthe compound of Example 188 (0.75 g, 3.2 mmol) in THF (5 mL). Thereaction mixture was stirred at -78° C. for 30 min, then methyl iodide(2.3 g, 16 mmol) was introduced in a single portion. This mixture wasstirred for 2.5 h at -78° C., then was warmed to -30° C., diluted withwater, and extracted with EtOAc. (2×). The combined organic extractswere dried (MgSO₄), concentrated, and purified by HPLC with 1:4EtOAc/cyclohexane to give 146 mg of the title compound as a light yellowsolid, an 18% yield. m.p. 101-103° C.

Example 192 2-Chloro-6-[(1,1-dimethylethyl)amino]-N-ethylbenzamide

A mixture of 2-chloro-6-fluorobenzaldehyde (99.1 g, 625 mmol) and NaN₃(81.2 g, 1249 mmol) in DMSO (900 mL) was slowly heated to 75° C. for 2h. The reaction temperature was then raised to 100° C. and the formationof the chloroanthranil was monitored to completion over about 3 h by ¹H-NMR analysis of the aromatic region. The dark solution was partitionedbetween water (2 liters) and ether, then filtered through celite tobreak up the emulsion. The aq layer was extracted with additional ether,then the combined organic extracts were washed with water, dried(MgSO₄), concentrated, and kugelrohr distilled to give 81.65 g of thechloroanthranil as a light yellow solid, an 85% yield. m.p. 45°-47° C.

A mixture of this chloroanthranil (81.65 g, 532 mmol) and tert-butanol(43.4 g, 586 mmol) was warmed to effect solution, then was cooled in anice-water bath while 70% perchloric acid was added at a rate whichmaintained the internal reaction temperature ≦35° C. After addition, thecold bath was removed and the reaction mixture continued to exotherm for.sup.˜ 1 h while a precipitate formed. After 2 h the resulting mixturewas cooled with an ice-water bath and slurried in ether (100 mL). Thesalts were collected by filtration, washed with dry ether, and driedunder vacuum to give 155.91 g of the N-tert-butyl chloroanthraniliumperchlorate salt as a pale yellow solid, a 95% yield.

This N-tert-butyl chloroanthranilium perchlorate salt (155.91 g, 503mmol) was added in portions, via Gooch tubing, to an ice-water cooledsolution of Et₃ N (152.7 g, 1509 mmol) in CH₂ Cl₂ (1 liter). Theresulting amber solution was stirred at RT for 30 min, then wasconcentrated to a small volume, diluted with dry ether (500 mL),filtered to remove the salts, and concentrated to give 101.11 g ofdesired b-lactam as a golden oil, a 96% yield.

A solution of this b-lactam (101.11 g, 483 mmol) in ether (100 mL) wasadded dropwise to an ice-water cooled solution of aq 70% EtNH₂ (465 g,7233 mmol), maintaining the internal reaction temperature ≦20° C. Theresulting mixture was stirred at RT for 30 min, then was diluted withwater and extracted with ether (3×). The combined organic extracts weredried (MgSO₄), concentrated to a small volume, then slurried in hexanes(1 liter) and filtered to give 111.75 g of the title compound as a whitesolid, a 91% yield. m.p. 139-140° C.

Example 193 2-Chloro-N-ethyl-4-formyl-6-(trimethylsilyl)benzamide

A mixture of 2-chloro-4-bromobenzoic acid (5.0 g, 21.2 mmol) andhexamethyldisilazane (5.0 mL, 23.7 mmol) was heated at 135° C. for 3 h,then was distilled under vacuum to afford 6.32 g of o-trimethylsilyl2-chloro-4-bromobenzoate as a colorless oil, a 97% yield.

A solution of 2.5M n-BuLi in hexanes (3.25 mL, 8.13 mmol) was added to adry-ice/acetone cooled solution of 2,2,6,6-tetramethylpiperidine (1.20g, 8.5 mmol) in THF (6 mL). This solution was stirred at -78° C. for 15min, then was cooled to -100° C. with ether/liquid N₂, and a solution ofO-trimethylsilyl 2-chloro-4-bromobenzoate (2.00 g, 6.5 mmol) in THF (6mL) was added slowly dropwise, maintaining the internal reactiontemperature ≦-95° C. The resulting reaction mixture was stirred at -100°C. for 15 min, then was poured into dilute aq citric acid and extractedwith ether (2×). The combined organic extracts were dried (MgSO₄), andconcentrated to give crude 2-chloro-4-bromo-6-trimethylsilylbenzoic acidas a golden oil.

The 2-chloro-4-bromo-6-trimethylsilylbenzoic acid was diluted withthionyl chloride (3 mL, 41.1 mmol) and warmed. When gas evolutionceased, the solution was concentrated and stripped from toluene (2×)under vacuum to remove the excess thionyl chloride. The remaining darkoil was dissolved in toluene (12 mL), then the compound from example k(2.2 g, 19.5 mmol) was added and the mixture was heated at 100° C. untilthe reaction was complete by GLC. The resulting mixture was cooled to 0°C., and Et₃ N (1.32 g, 13.0 mmol) was added in a single portion,followed by the dropwise addition of methanol (0.62 g, 19.4 mmol) intoluene (1 mL). The reaction was warmed to RT and monitored tocompletion by GLC, then was diluted with ether and extracted with sat aqNaHCO₃, dried (MgSO₄), concentrated, and the residue dissolved inhexanes. The hexane solution was cooled to -78° C. and filtered toremove insoluble impurities, then the filtrate was concentrated andpurified by RC with 1:49 EtOAc/hexanes to give 820 mg ofN-ethyl-N-(1-methoxy-2,2-dimethylpropyl)2-chloro-4-bromo-6-(trimethylsilyl)benzamide as a yellow oil.

A solution ofN-ethyl-N-(1-methoxy-2,2-dimethylpropyl)-2-chloro-4-bromo-6-(trimethylsilyl)benzamide(820 mg, 1.89 mmol) in THF (2 mL) was added dropwise to adry-ice/acetone cooled solution of 2.5M n-BuLi in hexanes (1 mL, 2.5mmol) in THF (2 mL). The resulting red solution was stirred at -78° C.for 15 min, then DMF (500 mL, 6.5 mmol) was added in a single portion.After 5 min, the reaction was poured into sat aq NaHCO₃ and extractedwith ether (2×). The combined organic extracts were dried (MgSO₄) andconcentrated, then a solution of this protected amide in acetone (5 mL)was charged with 6N HCl and stirred overnight at RT. The resultingmixture was poured into sat aq NaHCO₃ and extracted with ether (2×),then the combined organic extracts were dried (MgSO₄), concentrated, andpurified by RC with 3:7 EtOAc/hexanes to give 220 mg of the titlecompound as a white solid, a 40% yield. m.p. 95-97° C.

Example 194

2-[(1,1-Dimethylethyl)sulfinyl]-N-ethyl-6-fluoro-benzamide.

A mixture of 2-methyl-2-propanethiol (2.7 g, 30 mmol), the compound ofexample g (3.17 g, 15 mmol), and NaH (0.79 g, 33 mmol) in THF (100 mL)was stirred at RT for 1d, then at reflux for 1d. This was then quenchedwith sat aq NaHCO₃ (50 mL) and extracted with EtOAc (3×50 mL). Thecombined organic extracts were dried (MgSO₄), concentrated, and purifiedby HPLC with 1:4 EtOAc/hexanes to afford 3.5 g of2-[2-fluoro-6-(1,1-dimethylethylthio)phenyl]-4,4-dimethyl-2-oxazoline asa yellow oil, an 83% yield.

Following the procedure of example 6,2-[2-fluoro-6-(1,1-dimethylethylthio)phenyl]-4,4-dimethyl-2-oxazoline(3.5 g, 12.5 mmol) was converted toN-ethyl-2-fluoro-6-(1,1-dimethylethylthio)benzamide as a white solid.m.p 107-109° C.

A 0° C. solution of N-ethyl-2-fluoro-6-(1,1-dimethylethylthio)benzamide(3.45 g, 13.51 mmol) in methanol (100 mL) was combined with a 0° C.solution of OXONE® (8.31 g, 13.51 mmol) in water (100 mL). This mixturewas stirred for 2 min, then was poured into 25% aq sodium metabisulfite(100 mL) and extracted with ether (3×100 mL). The combined organics werewashed with brine followed with water, then was dried (MgSO₄),concentrated, and recrystallized from ethyl acetate-hexanes to afford2.2 g of the title compound as a white solid, a 60% yield. m.p. 114-116°C.

Example 195

N,N-Diethyl 2-[(1,1-dimethylethyl)sulfinyl]-6-fluoro-benzamide.

The title compound was prepared in an analogous procedure to Example194, and purified by RC with 1:1 ethyl acetate/hexanes to give a greenoil.

Example 196

N-(1-Methylethyl)-2-[(1,1-dimethylethyl)sulfinyl]-6-fluorobenzamide.

The title compound was prepared in an analogous procedure to Example194, and purified by recrystallization from ether/hexanes to give awhite solid. m.p. 120-135° C.

Example 197

N-(2-Chloroethyl)-2-fluoro-6-(2-methylphenyl)benzamide.

A 2.5M solution of n-BuLi in cyclohexane (6.4 mL, 16 mmol) was addeddropwise to an ether/liquid N₂ cooled solution of 2-bromotoluene (2.74g, 16 mmol) in THF (100 mL), maintaining the internal reactiontemperature ≦-85° C. The resulting solution was cannulated into anether/liquid N₂ cooled solution of the compound of example j (2.93 g, 16mmol) in THF (25 mL). The resulting mixture was warmed to -60° C. andpoured to sat aq NaHCO₃, then was extracted with ether (3×100 mL). Thecombined organic extracts were washed with water (2×25 mL), dried(MgSO₄), concentrated, then purified by HPLC with 3:7 EtOAc/hexanes toafford 3.2 g of 2-[2-fluoro-6-(2-methylphenyl)]-2-oxazoline as a whitesolid, a 78% yield. m.p. 65-68° C.

Excess HCl gas was bubbled into a solution of2-[2-fluoro-6-(2-methylphenyl)]-2-oxazoline (3.2 g, 12.5 mmol) in ether(50 mL). The resulting mixture was allowed to stir overnight, then wascrystallized by the addition of hexanes to afford 2.4 g of the titlecompound as a white solid, a 51% yield. m.p. 78-81° C.

Example 198

N-(2-Chloroethyl)-2-[(1,1-dimethylethyl)sulfinyl]-6-fluorobenzamide.

LiH (0.12 g, 16 mmol) was carefully added to a solution of1,1-dimethylethanethiol (1.44 g, 16 mmol) in THF (100 ml). When gasevolution ceased, the compound of example j (2.93 g, 16 mmol) was addedin a single portion. The mixture refluxed overnight, then was cooled andpartitioned between ether and sat aq NaHCO₃. The ether was dried (MgSO₄)and concentrated, then was dissolved in ether and excess HCl gas added.The resulting mixture was allowed to stir overnight, then wascrystallized by the addition of hexanes to afford 2.2 g ofN-(2-chloroethyl)-2-fluoro-6-(1,1-dimethyl-ethylthio)benzamide as awhite solid, a 47% yield.

A 0° C. solution ofN-(2-chloroethyl)-2-fluoro-6-(1,1-dimethylethylthio)benzamide (2.0 g,7.0 mmol) in methanol (50 mL) was combined with a 0° C. solution ofOXONE® (4.24 g, 7.0 mmol) in water (50 mL). This mixture was stirred for2 min, then was poured into 25% aq sodium metabisulfite (100 mL) andextracted with ether (3×100 mL). The combined organics were washed withbrine followed with water, then were dried (MgSO₄), concentrated, andpurified by HPLC with 7:3 ethyl acetate/hexanes to afford 2.1 g of thetitle compound as a white solid, a 98% yield. m.p. 80-90° C.

Example 199

N-(2-Chloroethyl)-2-fluoro-6-(1-methylcyclobutyl)-benzamide.

An 0.2M solution of lithium 4,4'-(di-t-butyl)biphenyl (50 mL, 10 mmol)was added to a dry ice/acetone cooled solution of1-chloro-1-methylcyclobutane (1.04 g, 10 mmol) in THF (25 mL),maintaining the internal reaction temperature ≦-55° C. The resultingmixture was stirred at -78° C. for 30 min, then the compound of examplej (1.65 g, 9 mmol) was added in a single portion. After 1 h at -78° C.,the reaction was poured into sat aq NaHCO₃ (50 mL) and extracted withether (3×50 mL). The combined organics were washed with water, dried(MgSO₄), concentrated, and purified by RC to afford 0.8 g of2-[2-fluoro-6-(1-methylcyclobutyl)]-2-oxazoline as a colorless oil, a34% yield. Excess HCl gas was bubbled into a solution of this oxazolinein ether. The resulting mixture was allowed to stir overnight, then wascrystallized by the addition of hexanes to afford 0.5 g ofN-(2-chloroethyl)-2-fluoro-6-(1-methylcyclobutyl)benzamide as a whitesolid, a 62% yield. m.p. 108-110° C.

Example 200

3,6-Dichloro-N-ethyl-2-(trimethylsilyl)benzamide.

2,5-Dichlorobenzoyl chloride (51 mmol) and 70% aq EtNH₂ (130 mmol) werecombined according to General Method El to afford 9.4 g ofN-ethyl-2,5-dichloro-benzamide as a beige solid, an 85% yield.

A solution of 1.5M LDA in THF (13 mL, 19.5 mmol) was added dropwise toan ether/liquid N₂ cooled solution of N-ethyl 2,5-dichlorobenzamide (2.0g, 9.2 mmol) and TMSCl (1.5 mL, 11.5 mmol) in THF (50 mL), maintainingthe internal reaction temperature ≦-80° C. The resulting reactionmixture was stirred at -100° C. for 30 min, then was partitioned betweenether and sat aq NaHCO₃. The ether solution was dried (MgSO₄),concentrated, and crystallized from EtOAc/hexanes to afford 1.15 g ofthe title compound as a white solid. m.p. 150-153° C.

Example 201

2-Chloro-N-ethyl-N-(1-methoxy-2,2-dimethylpropyl)-6-(trimethylsilyl)benzamide.

A solution of the compound of Example k (3.55 g, 31.4 mmol) in CH₂ Cl₂(10 mL) was added dropwise to an ice-water cooled solution of2-chlorobenzoyl chloride (5.0 g, 28.6 mmol) in CH₂ Cl₂ (20 mL). Thereaction was warmed to RT and exothermed for 10-15 min. The resultingsolution was cooled with an ice-water bath and Et₃ N (3.0 g, 29.6 mmol)was syringed in, followed by the dropwise addition of MeOH (1.83 g, 57.2mmol). The reaction was allowed to warm to RT and monitored tocompletion by GLC, then was diluted with ether and extracted with sat aqNaHCO₃, dried (MgSO₄), concentrated, and kugelrohr distilled undervacuum to afford 7.54 g ofN-ethyl-N-(1-methoxy-2,2-dimethylpropyl)-2-chlorobenzamide as acolorless oil, a 93% yield.

A solution of 1.3M s-BuLi in cyclohexane (3.53 mL, 4.59 mmol) was addedto a dry ice/acetone cooled solution of TMEDA (639 mL, 4.23 mmol) andN-ethyl-N-(1-methoxy-2,2-dimethylpropyl)-2-chlorobenzamide (1.0 g, 3.53mmol) in THF (7 mL). The resulting mixture was stirred at -78° C. for 45min, then TMSCl (671 mL, 5.29 mmol) was added in a single portion. Thereaction was allowed to warm to 0° C., and partitioned between ether and10% HCl. The ether solution was then extracted with sat aq NaHCO₃, dried(MgSO₄), and purified by RC with 1:49 EtOAc/hexanes to afford 750 mg ofthe title compound as a white solid, a 60% yield. m.p. 82-83° C.

Example 202

2-Chloro-6-(ethenylmethylphenylsilyl)-N-ethylbenzamide.

A 1.3M solution of s-BuLi in cyclohexane (10.5 mL, 13.6 mmol) was addedto a dry ice/acetone cooled solution of TMEDA (1 mL, 6.5 mmol) in THF(10 mL), followed by the dropwise addition of the compound of example f(1.0 g, 5.45 mmol) in THF (10 mL). Phenyl methyl vinyl chlorosilane (1.5g, 8.2 mmol) was added after 30 min, and the mixture was stirred at -78°C. for 2 h. This was poured into 25% aq citric acid and partitionedbetween EtOAc and water. The EtOAc was dried (MgSO₄), concentrated, andpurified by HPLC with 1:19 EtOAc/cyclohexane to afford 0.56 g of a whitesolid which was recrystallized from EtOAc/petroleum ether at lowtemperature to give 0.194 g of title compound, an 11% yield. m.p. 85-87°C.

Example 203

2,3-Dichloro-N-ethyl-6-(trimethylsilyl)benzamide.

2,3-Dichloro-6-(trimethylsilyl)benzoic acid was prepared from2,3-dichlorobenzoic acid according to the procedure of example a in 45%yield as 3.07 g of a white solid. m.p. 117-119° C.

This acid was converted to the acid chloride by the procedure of exampleb. The acid chloride was reacted with aq ethylamine using General MethodEl to afford the title compound. Purification by recrystallization fromhexanes gave 0.42 g of the title compound as white crystals in 58%yield. m.p. 96-98° C.

Example 204

2,3-Dichloro-N-(2-propenyloxy)-6-(trimethylsilyl)-benzamide.

The acid prepared in Example 203 was converted to the acid chloride bythe procedure of example b. The acid chloride was reacted with aqO-allylhydroxylamine using General Method El to afford the titlecompound. Purification by recrystallization from ether/hexanes gave 0.68g of the title compound as a white solid in 86% yield. m.p. 92-94° C.

Example 205

2,3-Dichloro-6-(trimethylsilyl)benzoic acid, 2,2-dimethylhydrazide.

The acid prepared in Example 203 was converted to the acid chloride bythe procedure of example b. The acid chloride was reacted with1,1-dimethylhydrazine using General Method El to afford the titlecompound. Purification by recrystallization from ether/hexanes gave 0.62g of the title compound as off-white crystals in 81% yield. m.p.144-145° C.

Example 206

2-Bromo-N-2-propynyl-6-(trimethylsilyl)benzamide.

The compound of Example d was reacted with propargylamine (3 eq)according to General Method El and the crude product was recrystallizedfrom hexanes to afford 0.55 g of the title compound as off-white needlesin 81% yield. m.p. 120-121° C.

Example 207

N-Ethyl-2-iodo-6-(trimethylsilyl)benzamide.

A mixture of the 2-iodobenzoic acid, hexamethyldisilazane (0.55-0.60 eq)and TMSCl (5 drops) was heated at 135° C. for 2-4 h. The reactionmixture was distilled under vacuum to afford the trimethylsilyl ester of2-iodobenzoic acid in 95% yield.

To a solution of 2,2,6,6-tetramethylpiperidine (1.1 eq) in THF at -78°C. was added a 1.6 M BuLi solution in hexanes (1.1 eq) dropwise. Thereaction solution was put in an ice bath (0° C.) for 1 h and cooled to-78° C. The trimethylsilyl benzoate prepared above was added dropwiseand stirred at -78° C. for 10-90 min. The reaction was quenched with sataq citric acid and extracted with ether. The ether layers were extractedwith 0.5 N NaOH and the basic aq layer was acidified with 2 N HCl andextracted with ether. The combined organic extracts were washed withbrine, dried (MgSO4) and concentrated to afford crude2-iodo-6-(trimethylsilyl)benzoic acid. The crude product was purified byrecrystallization from hexanes to afford 3.62 g of white needles in 75%yield. m.p. 126-133° C.

This acid was converted to the acid chloride by the procedure of exampleb. The acid chloride was reacted with 70% aq ethylamine using GeneralMethod El to afford the title compound. Purification byrecrystallization from hexanes gave 0.48 g of the title compound aswhite crystals in 88% yield. m.p. 135-137° C.

Example 208

2-Iodo-N-2-propynyl-6-(trimethylsilyl)benzamide.

The acid chloride prepared in Example 207 was reacted withpropargylamine (3 eq) using General Method El to afford the titlecompound. Purification by recrystallization from hexanes gave 0.48 g ofthe title compound as an off-white solid in 85% yield. m.p. 109-111° C.

Example 209

N-Cyclopropyl-2-iodo-6-(trimethylsilyl)benzamide.

The acid chloride prepared in Example 207 was reacted withcyclopropylamine (3 eq) using General Method El to afford the titlecompound. Purification by recrystallization from hexanes gave 0.49 g ofthe title compound as white needles in 87% yield. m.p. 162-164° C.

Example 210

2-[(Bromomethyl)dimethylsilyl]-6-chloro-N-ethyl-benzamide.

To a solution of the compound of example 45 (1.28 g, 5 mmol) in THF (30mL) at -78° C. was added a 1.7 M solution of t-BuLi in pentane (6.5 mL,11 mmol, 2.2 eq) such that the temperature was less than -70° C. Thereaction was stirred at -78° C. for 1.5 h and ethylene dibromide (0.52mL, 6.0 mmol, 1.2 eq) was added. The reaction was stirred for 15 min at-78° C. and worked up in the usual manner. The crude product waspurified by RC and recrystallized from aq methanol to afford the titlecompound as white needles (0.30 g, 18%). m.p. 98-99° C.

Example 211

[2-Chloro-6-(trimethylsilyl)benzoyl]ethylcarbamic acid,1,1-dimethylethyl ester.

To a solution of the compound of example 45 (3.83 g, 15 mmol) anddi-t-butyl carbonate (3.60 g, 16.5 mmol) in acetonitrile was added4-dimethylaminopyridine (0.18 g, 1.5 mmol). The solution was stirred atRT for 1 day, additional di-t-butyl carbonate (3.60 g) was added andstirring was continued for 3 days. Additional di-t-butyl carbonate (3.60g) was added and the reaction was stirred overnight and concentrated.The residue was diluted with ether, washed with sat citric acid, satNaHCO₃, brine, dried (MgSO₄) and concentrated to afford the titlecompound. The crude product was purified by flash chromatography (ethylacetate/hexanes) and recrystallization from hexanes (-78° C.) to affordthe title compound as a white solid (2.65 g, 50%). m.p. 51-52° C.

Example 212

2-Chloro-N-ethyl-6-(ethyldimethylsilyl)benzamide.

To a solution of the compound of example 45 (1.28 g, 5 mmol) and TMEDA(0.91 mL, 6.0 mmol, 1.2 eq) in THF at -78° C. was added a 1.7 M solutionof t-BuLi in pentane (7.1 mL, 12 mmol, 2.4 eq) such that the temperaturewas less than -70° C. The reaction was stirred at -78° C. for 2 h andmethyl iodide (0.44 mL, 7.0 mmol, 1.4 eq) was added. The reaction wasstirred for 15 min at -78° C. and worked up in the usual manner. Thecrude product was recrystallized from aq methanol and then from hexanesto afford the title compound as white crystals (0.62 g, 46%). m.p.94-95° C.

Example 213

5-Chloro-N-ethyl-2-(trimethylsilyl)benzamide.

2-Bromo-5-chlorobenzoic acid was converted to the acid chloride by theprocedure of example b. The acid chloride was reacted with 70% aqethylamine using General Method El to afford the amide. Purification byrecrystallization from methylcyclohexane/ethyl acetate gave 4.69 g of2-bromo-5-chloro-N-ethylbenzamide as a white solid in 75% yield. m.p.98-99° C.

To a solution of this amide (1.05 g, 4.0 mmol) in THF (20 mL) at -78° C.was added a 1.6 M solution of n-BuLi in hexanes (5.5 mL, 8.8 mmol, 2.2eq) dropwise such that the temperature was less than -70° C. The yellowsolution was stirred at -78° C. for 30 min and TMSCl (0.61 mL, 4.8 mmol,1.2 eq) was added dropwise. The solution was stirred at -78° C. for 45min and worked up in the usual manner. The crude product was purified byRC (ethyl acetate/hexanes) and recrystallization from hexanes to affordthe title compound as white needles (0.27 g, 26%). m.p. 104-105° C.

Example 214

N-Ethyl-5-nitro-2-(trimethylsilyl)benzamide.

To a solution of the amide of example 49 (1.10 g, 5 mmol) in CH₂ Cl₂ (50mL) at 0° C. was added dropwise over 2 min, a cold mixture of 70% nitricacid (0.95 mL, 15 mmol) and concentrated sulfuric acid (5 mL) dropwise.The mixture was stirred at 0° C. for 10 min and was poured onto ice. Themixture was extracted with ethyl acetate, the combined organic layerswashed with brine, sat NaHCO₃, brine, dried (MgSO₄) and concentrated toa solid (2.68 g, 101%) consisting of a 2:1 ratio of 5-nitro and 3-nitroisomers. The title compound was obtained by RC (ethyl acetate/hexanes)in 60% yield as a white solid. m.p. 100-102° C.

Example 215

6-Chloro-N-ethyl-3-nitro-2-(trimethylsilyl)benzamide.

To a solution of the amide of example 45 (1.28 g, 5 mmol) in CH₂ Cl₂ (20mL) at 0° C. was added dropwise a cold mixture of 70% nitric acid (0.64mL, 10 mmol) and concentrated sulfuric acid (5 mL) dropwise. The mixturewas stirred at 0° C. for 10 min and was poured onto ice. The mixture wasextracted with ether, the combined organic layers washed with satNaHCO₃, brine, dried (MgSO₄) and concentrated to a solid (1.52 g, 101%).The title compound was obtained by recrystallization from ethylacetate/hexanes in 83% yield as a white solid. m.p. 147-149° C.

Example 216

2-Chloro-N-ethyl-3-nitro-6-(trimethylsilyl)benzamide.

The mother liquors from Example 215 were purified by RC (ethylacetate/hexanes) to give 0.11 g of the title compound in 7% yield as awhite solid. Recrystallization from ethyl acetate/hexanes afforded puretitle compound. m.p. 126-127° C.

Example 217

5-Amino-N-ethyl-2-(trimethylsilyl)benzamide.

A solution of the crude amide of Example 214 (2.67 g, 10 mmol) inethanol (50 mL) with 10% palladium/carbon (0.3 g) was hydrogenated at 50psi for 3 h. The catalyst was filtered off through Celite and thesolution concentrated. The crude product was purified by RC (ethylacetate/hexanes) and recrystallized from ethyl acetate/hexanes to affordthe title compound as a white solid (0.64 g, 27%). m.p. 143-145° C.

Example 218

3-Chloro-N-ethyl-2-fluoro-6-(trimethylsilyl)benzamide.

The trimethylsilyl ester of 3-chloro-2-fluorobenzoic acid (11.66 g) wasprepared in 84% yield using the method described in Example 207. Thisester (2.47 g) was converted to 0.45 g of3-chloro-2-fluoro-6-(trimethylsilyl)benzoic acid in 18% yield using themethod of Example 207. The crude product was converted to the acidchloride by the procedure of example b. The acid chloride was reactedwith 70% aq ethylamine using General Method El to afford the titlecompound. Purification by flash chromatography (ethyl acetate/hexanes)followed by recrystallization from pentane gave 84 mg of the titlecompound as an off-white solid (18%). m.p. 96-97° C.

Example 219

2-Chloro-N-ethyl-3-methoxy-6-(trimethylsilyl)benzamide.

2-Bromo-5-methoxybenzoic acid was converted to the acid chloride by theprocedure of example b. The acid chloride was reacted with 70% aqethylamine using General Method El to afford 24.44 g of2-chloro-N-ethyl-3-methoxybenzamide in 95% yield.

This amide (2.58 g, 10 mmol) was dissolved in concentrated sulfuric acid(5 mL) and N-chloro-succinimide (1.47 g, 11 mmol) was added portion-wiseover 15 min. The mixture was stirred for 2 h and was poured into icewater. The mixture was extracted with ethyl acetate, washed with 1.25 NNaOH, sat sodium sulfite, brine, dried (MgSO₄) and concentrated toafford a white solid. The crude product was purified byrecrystallization from ethyl acetate/hexanes to afford6-bromo-2-chloro-N-ethyl-3-methoxybenzamide as white needles (1.92 g,66%). m.p. 181-182° C.

To a solution of this amide (0.58 g, 2.0 mmol) in THF (20 mL) at -78° C.was added a solution of 1.6 M n-BuLi in hexanes (2.8 mL, 4.4 mmol). Thereaction was stirred for 1 h at -78° C., allowed to warm to -30° C. andcooled to -78° C. TMSCl (0.30 mL, 2.4 mmol) was added, the reactionmixture allowed to warm to -30° C. and worked up in the usual manner.The crude product was purified by RC (ethyl acetate/hexanes) andrecrystallized from hexanes to afford the title compound as an off-whitesolid (45 mg, 4%). m.p. 136-137° C.

Example 220

3-Bromo-2-chloro-N-ethyl-6-(trimethylsilyl)benzamide.

To a solution of the compound of Example 201 (0.79 g, 2.2 mmol) andTMEDA (0.44 mL, 2.9 mmol) in THF (20 mL) at -78° C. was added a solutionof 0.86 M s-BuLi in cyclohexane (3.3 mL, 2.9 mmol). The reaction wasstirred at -78° C. for 30 min and 1,2-dibromoethane (0.26 mL, 3.0 mmol)was added. The reaction was stirred for 15 min at -78° C. and wasquenched with sat NaHCO₃. The mixture was extracted with ether, washedwith brine, dried (MgSO₄) and concentrated to afford a yellow oil. Thisoil was dissolved in a mixture of acetone (30 mL) and 6 N HCl (15 mL)and was stirred overnight. The mixture was concentrated, extracted withether, the organic layers washed with brine, dried (MgSO₄) andconcentrated to afford the title compound as a clear oil. The crudeproduct was purified by RC (ethyl acetate/hexanes) and wasrecrystallized from pentane (-78° C.) to afford 76 mg of a white solid(10% yield). m.p. 105-106° C.

Example 221

N-Ethyl-2-phenyl-6-(trimethylsilyl)benzamide.

2-Phenylbenzoic acid was converted to the acid chloride by the procedureof example b. The acid chloride was reacted with 70% aq ethylamine usingGeneral Method El to afford 10.59 g of N-ethyl-2-phenylbenzamide in 94%yield. m.p. 77-79° C.

This amide (2.25 g, 10 mmol) and TMEDA (1.2 eq) in THF were mixed andcooled to -78° C. and a 1.3 M s-BuLi solution in cyclohexane (2.2 eq)was added dropwise. The resulting reaction mixture was stirred at -78°C. for 30 min and TMSC1 (1.2 eq) was added dropwise. The reaction wasstirred at -78° C. for 30 min and allowed to warm to -30° C. Thereaction was worked up in the usual manner. The crude product waspurified by flash chromatography and recrystallization from hexanes toafford the title compound as a white solid (1.15 g, 39%). m.p. 159-160°C.

Example 222

5-(Dimethylamino)-N-ethyl-N-(1-methoxy-2,2-dimethylpropyl)-2-(trimethylsilyl)benzamide.

A solution of the compound of Example 201 (0.72 g, 2.0 mmol) and TMEDA(1.20 mL, 8.0 mmol) in THF (30 mL) at -78° C. was treated with asolution of 1.7 M t-BuLi in pentane (5.6 mL, 9.6 mmol) and allowed toslowly warm to -20° C. over 4 h. The reaction was quenched with1,2-dibromoethane (0.86 mL, 10 mmol), was diluted with sat NaHCO₃,extracted with ether, the organic layers washed with brine, dried(MgSO₄) and concentrated to afford the title compound. The crude productwas purified by RC (ethyl acetate/hexanes) and recrystallization frompentane (-78° C.) to afford the title compound as a white solid (0.14 g,20%). m.p. 96-98° C.

Example 223

2-Chloro-N-ethyl-3-formyl-6-(trimethylsilyl)benzamide.

The method of Example 230 was followed, substituting DMF (2 eq) for MeIto afford the title compound. The crude product was purified byrecrystallization from ethyl acetate/hexanes to afford 1.16 g of thetitle compound as white needles in 82% yield. m.p. 140-142° C.

Example 224

2-Chloro-3-(difluoromethyl)-N-ethyl-6-(trimethylsilyl)-benzamide.

A solution of the compound of Example 223 (0.26 g, 0.92 mmol) in CH₂ Cl₂(10 mL) at 0° C. was treated with DAST (0.12 mL, 0.92 mmol) and kept for22 h. The reaction was poured into water, extracted with ether, theorganic layers washed with sat NaHCO₃, brine, dried (MgSO₄) andconcentrated to afford the title compound. The crude product waspurified by recrystallization from hexanes to afford 0.20 g of the titlecompound (70%) as off-white crystals. m.p. 120-121° C.

Example 225

N-Ethyl-5-(trifluoromethyl)-2-(trimethylsilyl)benzamide.

3-Trifluoromethylbenzoic acid was converted to the acid chloride by theprocedure of example b. The acid chloride was reacted with 70% aqethylamine using General Method El to afford the title compound.Purification by recrystallization from hexanes gave 2.24 g ofN-ethyl-3-(trifluoromethyl)benzamide as a white needles in 19% yield.m.p. 98-99° C.

This amide was reacted with TMSCl (1.3 eq) as in Example 221 to affordthe title compound. The crude product was purified by RC (ethylacetate/hexanes) and recrystallization from pentane (-78° C.) to afford0.14 g (5%) of the title compound as a white solid. m.p. 101-102° C.

Example 226

5-(Dimethylamino)-N-ethyl-2-(trimethylsilyl)benzamide.

The compound of Example 222 (0.31 g, 0.85 mmol) was dissolved in CH₂ Cl₂(20 mL) and was treated with iodotrimethylsilane (2.1 mL, 15 mmol) in afoil-covered flask. The reaction was stirred for 2 h and was quenchedwith sat NaHCO₃. The mixture was extracted with ether, the organiclayers were washed with brine and sat sodium bisulfite, dried (MgSO₄)and concentrated to afford the title compound. The crude product waspurified by RC (ethyl acetate/hexanes) and recrystallized from hexanesto afford 68 mg (5%) of the title compound as a white solid. m.p.141-143° C.

Example 227

2-Chloro-N-ethyl-3-(hydroxymethyl)-6-(trimethylsilyl)-benzamide.

To a solution of sodium borohydride (50 mg, 1.2 mmol) in ethanol (20 mL)was added the compound of Example 222 (0.62 g, 2.2 mmol). The mixturewas stirred 45 min, was diluted with water and treated with potassiumdihydrogenphosphate. The mixture was extracted with ethyl acetate, theorganic layers washed with brine, dried (MgSO₄) and concentrated toafford the title compound. The crude product was purified byrecrystallization from ethyl acetate/hexanes to afford white crystals(0.51 g, 82%). m.p. 244-245° C.

Example 228

2-Chloro-N-ethyl-3-(fluoromethyl)-6-(trimethylsilyl)-benzamide.

A solution of the compound of Example 227 (0.29 g, 1.0 mmol) in CH₂ Cl₂(20 mL) was treated with DAST (0.26 mL, 2.0 mmol) and stirred for 1 h.The reaction was poured into water, extracted with ether, the organiclayers washed with brine, dried (MgSO₄) and concentrated to afford thetitle compound. The crude product was purified by RC (ethylacetate/hexanes) and recrystallization from hexanes to afford 0.20 g ofthe title compound (71%) as white crystals. m.p. 104-105° C.

Example 229

2-Chloro-3-cyano-N-ethyl-6-(trimethylsilyl)benzamide.

A solution of the compound of Example 223 (0.28 g, 1.0 mmol) andhydroxylamine hydrochloride (0.12 g, 1.7 mmol) in pyridine (10 mL) wasstirred at RT for 2 h. Acetic anhydride (0.75 mL, 8.0 mmol) was addedand the solution was heated at 100° C. for 1.5 h. The mixture wasconcentrated, water added and the mixture extracted with ether. Theorganic layers were washed with 0.5 N HCl, sat NaHCO₃, brine, dried(MgSO₄) and concentrated to afford the title compound. The crude productwas purified by recrystallization from ethyl acetate/hexanes to afford0.21 g of white needles (74%). m.p. 111-112° C.

Example 230

2-Chloro-N-ethyl-3-methyl-6-(trimethylsilyl)benzamide.

A solution of the compound of Example 201 and TMEDA (1 eq) in THF/ether(1:1) at -100° C. was treated dropwise with a solution of 1.3 M s-BuLiin cyclohexane in hexanes (2.0-2.2 eq) such that the temperature wasless than -95° C. The reaction was stirred at -100° C. for 30 min, MeI(2.2 eq) was added and the reaction was allowed to warm to -30° C. Thereaction was worked up in the usual manner.

The crude product was hydrolyzed to the N-ethylbenzamide by dissolutionin dioxane (7.5 mL/mmol) and addition of conc HCl (2.5 mL/mmol). Themixture was stirred at RT for 1.5 h and brine was added. The mixture wasextracted with ether, the organic extracts washed with sat NaHCO₃,brine, dried (MgSO₄) and concentrated. The crude product was purified byrecrystallization from hexanes followed by recrystallization from aqmethanol (2 times) to afford 0.18 g of the title compound as whiteneedles in 27% yield. m.p. 120-122° C.

Example 231

2-Chloro-N-ethyl-3-(methylthio)-6-(trimethylsilyl)-benzamide.

The method of Example 230 was followed, substituting methylmethanethiolsulfonate (2.2 eq) for methyl iodide to afford the titlecompound. The crude product was purified by recrystallization from ethylacetate/hexanes to afford 1.12 g of the title compound as white needlesin 74% yield. m.p. 137-139° C.

Example 232

3-Bromo-6-chloro-N-ethyl-2-(trimethylsilyl)benzamide.

2-Chloro-5-bromobenzoic acid (20 g, 0.08 mol) in CH₂ Cl₂ (50 mL) wastreated with oxalyl chloride (30 mL, 0.34 mol) and DMF (catalytic) for 2h at RT. The reaction mixture was concentrated under vacuum to give theacid chloride. The acid chloride was reacted with ethyl amine asdescribed in Method E2 to give 2-chloro-5-bromo-N-ethylbenzamide.

LDA was formed by adding 2.5 M n-BuLi (1.7 mL, 0.004 mol) todiisopropylamine (0.6 mL, 0.004 mol) in 10 mL THF at -78° C. The mixturewas warmed briefly to 0° C. then cooled to -78° C. A solution of theabove compound in THF (5 mL) was added. After 0.5 h at -78° C. TMSCl(0.31 mL, 0.0024 mol) was added. The reaction mixture was warmed to -40°C. and poured into aq NaHCO₃ and extracted with ether. The ether extractwas washed with water and brine, dried (MgSO₄) and concentrated. Thecrude product was purified by flash chromatography (0-15% ethylacetate/hexanes) to give the title compound as a white solid (0.2 g) in32% yield. m.p. 155-157° C.

Example 233

3-Amino-6-chloro-N-ethyl-2-(trimethylsilyl)benzamide.

A mixture of the compound of Example 215 (6.85 g, 0.023 mol) and PtO₂(catalytic) in ethanol was placed on the Parr Hydrogenator for 16 h. Thereaction mixture was filtered through celite and concentrated. Theresulting solid was dissolved in CH₂ Cl₂ and filtered through silica gelthree times. The filtrate was concentrated to give the title compound asa yellow solid in 13% yield. m.p. 147-149° C.

Example 234

2,4-Dichloro-N-ethyl-6-(trimethylsilyl)benzamide.

The 2,4-dichloro-N-ethyl benzamide (5.8 g, 0.027 mol) was prepared in92% yield from 2,4-dichlorobenzoyl chloride (4 ml, 0.03 mol) and ethylamine (70 wt % in H₂ O) using Method E2.

1.5 M LDA in THF was added dropwise to a solution of the above amide (2g, 0.01 mol) and TMSCl (1.5 ml, 0.011 mol) in THF, cooled to -100° C.under nitrogen. After 30 min the reaction mixture was poured into diluteaq NaHCO₃ and extracted with ether. The ether extract was washed withwater and brine, dried (MgSO₄) and concentrated. The crude product wasfiltered through silica gel with a gradient elution of ethylacetate/hexanes and concentrated to give the title compound as a whitesolid in 19% yield. m.p. 101-103° C.

Example 235

2-Chloro-4-(1,1-dimethylethyl)-N-ethyl-6-(trimethylsilyl)benzamide.

4-t-Butyl-N-ethylbenzamide (9 g, 0.044 mol) was prepared in 97% yieldfrom 4-t-butylbenzoyl chloride (9 ml, 0.045 mol) and ethyl amine (70 wt% in water) using Method E2.

1.3 M s-BuLi in cyclohexane (41 mL, 0.053 mol) was added dropwise to asolution of the above amide (5 g, 0.024 mol) and TMEDA (4 ml, 0.027 mol)in THF, cooled to -78° C. under nitrogen. After 30 min a solution ofhexachloroethane (6.4 g, 0.027 mol) in THF was added. After 0.5 h at-78° C. the reaction mixture was warmed to -30° C. and poured intodilute aq NaHCO₃ and extracted with ether. The ether extract was washedwith water and brine, dried (MgSO₄) and concentrated. The resultingsolid was recrystallized from cyclohexane to give 5 g of2-chloro-4-t-butyl-N-ethylbenzamide, a white solid.

To a solution of the above compound (2.5 g, 0.01 mol) and TMEDA (1.66mL, 0.011 mol) in THF, cooled to -78° C. under nitrogen, was added 1.3 Ms-BuLi in cyclohexane (17 mL, 0.022 mol) dropwise. After 0.5 h TMSCl(1.6 mL, 0.0125 mol) was added. The reaction mixture was stirred at -78°C. for 45 min then warmed to -30° C. and poured into dilute aq NaHCO₃and extracted with ether. The ether extract was washed with water andbrine, dried (MgSO₄) and concentrated. The crude product was purified byflash chromatography (0-10% ethyl acetate/hexanes) to give the titlecompound as a white solid (0.78 g) in 25% yield. m.p. 124-126° C.

Example 236

6-Bromo-N-ethyl-3-methoxy-2-(trimethylsilyl)benzamide.

2-Bromo-5-methoxybenzoic acid was converted to the acid chloridefollowing example b and then to the ethyl amide using Method El.

A solution of the ethyl amide (1 g, 0.004 mol) and TMSCl (0.63 mL, 0.005mol) in THF (15 mL) was cooled to -100° C. under nitrogen and 2 M LDA(4.5 mL, 0.009 mol) was added dropwise. After stirring at -78° C. for0.5 h the reaction mixture was poured into aq NaHCO₃ and extracted withether. The ether extract was washed with water and brine, dried (MgSO₄)and concentrated. The crude product was triturated with ether and theresulting solid was recrystallized from aq ethanol to give the titlecompound as a white solid (100 mg) in 8% yield. m.p. 200° C.

Example 237

6-Chloro-3-(dimethylamino)-N-ethyl-2-(trimethylsilyl)-benzamide.

2-Chloro-5-nitro-N-ethylbenzamide was prepared from the correspondingacid using the Method of Example 232. A solution of this compound (25 g,0.11 mol) in ethyl acetate (250 mL), water (75 mL) and glacial aceticacid (325 mL) was heated then iron powder (25 g, 0.44 mol) was added.The reaction mixture exothermed and gas evolution was vigorous for 1 h,even though it was cooled with an ice bath. When gas evolution ceasedthe reaction mixture was poured into water and CH₂ Cl₂ and filtered toremove the remaining iron. The filtrate was extracted with CH₂ Cl₂several times. The organic layers were combined and washed with waterand brine, dried (MgSO₄) and concentrated to give2-chloro-5-amino-N-ethylbenzamide as an oil (12.5 g, 57% yield).

A mixture of the above amine (3 g, 0.015 mol), potassium carbonate (3.8g, 0.028 mol) and MeI (1.4 mL, 0.022 mol) in DMF stirred at RTovernight. The reaction mixture was poured into water and extracted withether. The ether layer was washed with water and brine, dried (MgSO₄)and concentrated to give an oil. Purification by flash chromatography(0-50% ethyl acetate/ hexanes) gave N-ethyl2-chloro-5-(dimethylamino)benzamide as a yellow solid in 29% yield.

A solution of the above compound (0.65 g, 0.003 mol) in THF was stirredat -78° C. under nitrogen. 1.7 M t-BuLi in pentane was added. After 0.5h at -78° C. a solution of TMSCl in THF was added. After 1 h at -78° C.the reaction mixture was poured into aq NaHCO₃ and extracted with ether.The ether extract was washed with water and brine, dried (MgSO₄) andconcentrated. The crude product was triturated with a mixture ofhexanes/CH₂ Cl₂ /ethyl acetate and filtered to give the title compoundas a white solid (0.100 g) in 11% yield. m.p. 179-180° C.

Example 238

2-Chloro-N-ethyl-3-(methylsulfonyl)-6-(trimethylsilyl)-benzamide.

To a solution of the compound of Example 231 (0.30 g, 1.0 mmol) in CH₂Cl₂ (20 mL) at RT was added m-chloroperbenzoic acid (0.59 g, 3.4 mmol).The reaction was stirred for 7 h, was washed with sat NaHCO₃, brine,dried (MgSO₄) and concentrated to afford the title compound. The crudeproduct was purified by recrystallization from ethyl acetate/hexanes toafford white needles (0.26 g, 79%). m.p. 139-140° C.

Example 239

2-Chloro-N-ethyl-3-iodo-6-(trimethylsilyl)benzamide.

The method of Example 230 was followed, substituting 1,2-diiodoethane(2.3 eq) for MeI, to afford the title compound. The crude product waspurified by flash chromatography (ethyl acetate/hexanes) andrecrystallization from aq methanol to afford 2.72 g of the titlecompound as white crystals in 71% yield. m.p. 128-130° C.

Example 240

5-(Benzoylamino)-N-ethyl-2-(trimethylsilyl)benzamide.

To a solution of the compound of Example 217 (0.118 g, 0.5 mmol) in CH₂Cl₂ (10 mL) was added triethylamine (0.14 mL, 1.0 mmol), benzoylchloride (70 μL, 0.6 mmol) and 4-dimethylaminopyridine (12 mg). Thereaction was stirred at RT for 16 h, diluted with water, and extractedwith ethyl acetate. The extracts were washed with 0.04 N HCl, satNaHCO₃, brine, dried (MgSO₄) and concentrated to afford the titlecompound. The crude product was purified by recrystallization from ethylacetate/hexanes to afford the title compound as fluffy white crystals(0.129 g, 76%). m.p. 185-187° C.

Example 241

2-Chloro-N-ethyl-3-(2-(E)-nitro-ethenyl)-6-(trimethylsilyl)benzamide.

To a solution of the compound of Example 223 (0.199 g, 0.7 mmol) inmethanol (5 mL) at 0° C. was added nitromethane (0.3 mL, 5.0 mmol) and2.5 N NaOH (2.3 mL, 5.8 mmol) portionwise over 2 h. The suspension wasdissolved by addition of ice-cold water and cold 2 N HCl (10 mL) wasadded. The precipitate was filtered and washed with water to afford thecrude title compound. The crude product was purified byrecrystallization from aq methanol to afford the title compound as alight yellow fluffy solid (60 mg, 26%). m.p. 104-106° C.

Example 242

2-Chloro-N-ethyl-3-phenyl-6-(trimethylsilyl)benzamide.

To a solution of the compound of Example 239 (0.191 g, 0.5 mmol) andpalladium tetrakistriphenylphosphine (23 mg, 0.02 mmol) in toluene (10mL) was added 2 M sodium carbonate (0.5 mL) and phenyl boronic acid (73mg, 0.6 mmol). The mixture was heated at 90° C. for 30 h, additionalportions of catalyst (20 mg) and 2 M sodium carbonate (0.5 mL) wereadded and heating was continued for 24 h. The cool reaction was dilutedwith CH₂ Cl₂ and washed with 2 M sodium carbonate (50 mL with 5 mL concNH₄ OH). The organic layer was dried (MgSO₄) and concentrated. The crudeproduct was purified by RC (ethyl acetate/hexanes) and recrystallizationfrom hexanes to afford the title compound as white needles (98 mg, 59%).m.p. 134-135° C.

Example 243

3-Acetyl-2-chloro-N-ethyl-6-(trimethylsilyl)benzamide.

To a solution of the compound of Example 223 (0.284 g, 1.0 mmol) in THF(20 mL) at -78° C. was added a 1.4 M solution of methyl lithium in ether(3.2 mL, 4.4 mmol) portionwise over 1 h. The reaction mixture wasstirred for an additional hour at -78° C. and was quenched with satcitric acid. The mixture was extracted with ethyl acetate and theorganic layers were washed with brine, dried (MgSO₄) and concentrated toafford the secondary alcohol as an oil.

A solution of the crude alcohol in ethyl acetate was added to a slurryof pyridinium chlorochromate (0.54 g, 2.5 mmol) in CH₂ Cl₂ (50 mL). Theslurry was stirred for 3 days, ether (100 mL) was added and the slurrywas filtered through a pad of silicia gel and concentrated to afford thetitle compound as an oil. The crude product was purified by RC (ethylacetate/hexane), followed by recrystallization from ether/hexanes toafford the title compound as white needles (0.126 g, 42%). m.p. 78-80°C.

Example 244 2-Chloro-3-[(ethylamino)carbonyl]-4-(trimethylsily)- benzoicacid, methyl ester.

To a solution of silver nitrate (0.71 g, 4.2 mmol) in water (20 mL) wasadded 2.5 N Naoh (3.4 mL, 8.2 mmol) giving a brown suspension. Asolution of the aldehyde of Example 223 (0.56 g, 2.0 mmol) in THF (25mL) was added and the mixture was stirred at RT for 2 h. The mixture wasfiltered through Celite, diluted with water and washed with CH₂ Cl₂. Theaq solution was acidified with 2 N HCl and extracted with CH₂ Cl₂. Theorganic layers were washed with brine, dried (MgSO₄) and concentrated toafford the crboxylic acid as a white solid (0.57 g, 95%).

The carboxylic acid was converted to the acid chloride by the procedureof eaxmple b.

To a solution of the acid chloride (0.48 mmol) in toluene (10 mL) wasadded triethylamine (0.139 mL, 1.0 mmol) and methanol (0.08 mL, 2.0mmol). The reaction was stirred at RT for 16 h, diluted with sat NaHCO₃and extracted with ethyl acetate. The organic layers were washed withbrine, dried (MgSO₄) and concentrated to afford the title compound. Thecrude product was purified by recrystallization from ether/hexanes at-78° C. to afford the title compound as a white solid (0.014 g, 69%),m.p. 103-104° C.

Example 245 N-Ethyl-5-isothiocyanato-2-(trimethylsilyl)benzamide.

To a solution of the compound of Example 217 (0.354 g, 1.5 mmol) in CH₂Cl₂ (25 mL) was added 1,1'- thiocarbonyl-2(1H)pyridone (0.35 g, 1.5mmol). The solution was stirred at RT for 40 min, was diluted with CH₂Cl₂ and washed with water, brine, dried (MgSO₄) and concentrated toafford the title compound. The crude product was purified by flashchromatography (CH₂ Cl₂), followed by recrystallization from hexanes toafford the title compound as white needles (0.336 g, 81%). m.p.106.5-108° C.

Example 246

N-Ethyl-3-nitro-2-(trimethylsilyl)benzamide.

The title compound was obtained as the minor product in the preparationof Example 214 by RC (ethyl acetate/hexanes). The crude product wasrecrystallized from ether/hexanes and dried at 65° C. @0.05 mm to affordthe title compound as white needles (0.656 g, 25%). m.p. 84-86° C.

Example 247

N-Ethyl-2-(1,1-dimethylethoxy)benzamide.

2-Iodobenzoic acid (65.92 g, 0.266 mol), oxalyl chloride (40.5 g, 0.319mol), CH₂ Cl₂ (200 mL) and DMF (10 drops) were stirred at RT overnight.The reaction solution was concentrated, toluene was added and thesolution concentrated to afford the crude 2-iodobenzoyl chloride.

The acid chloride was reacted with 70% aq ethyl amine using GeneralMethod El to afford N-ethyl-2-iodobenzamide as a tan solid (70.80 g,97%).

Potassium t-butoxide (12.25 g, 0.109 mol) was dissolved in pyridine (50mL) and cuprous chloride (10.81 g, 0.109 mol) was added. The blacksuspension was stirred at RT for 30 min and N-ethyl-2-iodobenzamide(10.00 g, 36.4 mmol) dissolved in pyridine (20 mL) was added dropwise.The mixture was stirred at room temperature for 1 h and was poured in aqammonium hydroxide and extracted with ether. The organic extracts werewashed with 1 N NaOH, brine, dried (MgSO₄) and concentrated to afford abrown semi-solid. The crude product as purified by flash chromatography(ethyl acetate/hexanes) to afford the title compound as a light yellowsolid (2.36 g, 29%). m.p. 34.5-36° C.

Examples 248 & 249

Example 248: N-Ethyl-3-(trimethylsilyl)-2-thiophenecarboxamide.

Example 249: N-Ethyl-3,5-bis(trimethylsilyl)-2-thiophenecarboxamide.

(a) A mixture of 20 g of 2-thiophenecarboxylic acid and 30 mL thionylchloride was heated at reflux for 2.5 h, then cooled and concentrated invacuo to give 21 g of crude 2-thiophenecarboxylic acid chloride as anamber oil.

(b) A solution of 2-thiophenecarboxylic acid chloride (7.3 g, 50 mmol)in 30 mL CH₂ Cl₂ was added to 70% ethylamine in water (11 g) at -5° C.and the resulting solution was stirred at RT for 18 h. After that, waterwas added. The organic layer was separated, washed with water, brine,dried and concentrated. Purification of the residue by flashchromatography with 25% ethyl acetate-hexane gave 6.4 g (83.1% yield) ofN-ethyl-2-thiophenecarboxamide as a white solid, m.p. 75-78° C.

(c) A solution of 2.5M n-BuLi in hexane (18 mL) was added dropwise to asolution of N-ethyl-2-thiophenecarboxamide (3.1 g, 20 mmol) in 50 mL THFat below -65° C. under a positive nitrogen atmosphere and the resultingsolution was stirred at -70° C. for 45 min. After that, TMSCl (9 mL) wasadded slowly at below -60° C. and stirring was continued at below -60°C. for 15 min. The solution was allowed to warm to 0° C., then pouredinto water and extracted with CH₂ Cl₂. The organic layer was separated,washed with brine, dried and concentrated. Flash chromatography of theresidue with 5% ethyl acetate-hexane yielded 3.1 g of Example 248 as awhite solid, m.p. 81-84° C., and 1.1 g of Example 249 as a colorlessoil. n_(D) ²⁴ 1.5228.

Example 250

N,N-Diethyl-2,4-bis(trimethylsilyl)-3-furancarboxamide.

a) To a solution of diisopropylamine (10 g, 0.1 mol) in 90 mL THF undera positive nitrogen atmosphere was added 2.5M n-BuLi in hexane (40 mL,0.1 mol) at below -20° C. and the resulting solution was stirred atbelow -20° C. for 0.5 h, then cooled to -70° C. and a solution of3-furoic acid (5.1 g, 46 mmol) in 50 mL THF was added, maintaining thetemperature at below -70° C. After the addition was complete, stirringat -70° C. was continued for 1 h. Then 20 mL TMSCl was added dropwise at-70° C. and the reaction solution was stirred at -70° C. for 0.5 h, thenallowed to warm to RT and poured into a mixture of CH₂ Cl₂₁ ice-waterand 2N HCl. The aq layer was separated and extracted with CH₂ Cl₂. Thecombined organic layers were washed with brine, dried and concentratedto give a mixture of 2-(trimethylsilyl)-3-furoic acid and2,4-bis(trimethylsilyl)-3-furoic acid.

b) A mixture of 3-furoic acid chlorides (prepared from a mixture ofacids (1.4 g) of step a, 6 mL thionyl chloride and a catalytic amount ofDMF according to the method of Example 248a was reacted with 4 g ofdiethylamine as in Example 248b. The crude mixture was purified by flashchromatography with 10% ethyl acetate-hexane to give 0.1 g of the titlecompound as a greenish oil. n_(D) ²⁵ 1.4812.

Example 251 & 252

Example 251: N-Ethyl-3,5-bis(trimethylsilyl)-2-furancarboxamide.

Example 252: N-Ethyl-3-(trimethylsilyl)-2-furancarboxamide.

Using the method of Examples 248 and 249, 2-furoic acid was converted to2.7 g of Example 251 as a white solid, m.p. 99-102° C., and 1 g ofExample 252 as a white solid. m.p. 69-72° C.

Example 253

N-Ethyl-1-[(trimethylsilyl)methyl]-1H-pyrrole-2-carboxamide.

A mixture of 1-methyl-2-pyrrolecarboxylic acid (10 g, 80 mmol) in 25 mLoxalyl chloride containing 6 drops of DMF was refluxed for 1 h, thencooled to RT and excess oxalyl chloride was removed in vacuo. The crudeacid chloride was dissolved in CH₂ Cl₂ and added slowly to 40 mL 70% aqethylamine at between --15 and -10° C. The reaction solution was stirredat RT for 1 h, then poured into water and extracted with CH₂ Cl₂. Theorganic solution was washed with brine, dried and concentrated. Theresidue was purified by flash chromatography with 25% ethylacetate-hexane to provide 9.5 g of desired product as a light yellowsolid.

To the ethyl amide (1.5 g, 10 mmol) in 16 mL THF under a positivenitrogen atmosphere was added 12 mL 2.5M of n-BuLi in hexane at around30° C. and the resulting solution was stirred at ambient temperature for1 h. Then 6 mL TMSCl was added slowly at 0° C. and stirring wascontinued at ambient temperature for 1 h. After that, the solution waspoured into ice-water and extracted with CH₂ Cl₂. The organic solutionwas washed with water, brine, dried and concentrated in vacuo. Flashchromatography of the residue with 10% ethyl acetate-hexane gave 0.6 gof desired product as an orange oil. n_(D) ²⁵ 1.5185.

Example 254

5-Chloro-N-ethyl-3-(trimethylsilyl)-2-thiophene-carboxamide.

The title compound was prepared from 5-chloro-2-thiophenecarboxylic acidusing the methods of Example 248 yielding 1.5 g as a white solid. m.p.105-108° C.

Example 255

N,N-Diethyl-3-(trimethylsilyl)-2-thiophenecarboxamide.

To a solution of the compound of Example 248 (1.1 g, 5 mmol) in 10 mLTHF under a positive nitrogen atmosphere was added dropwise 2.4 mL 2.5Mn-BuLi in hexane at -40° C. Stirring was continued at between -30 and-20° C. for 1 h. After that, 2 g ethyl iodide was added dropwise. Theresulting reaction solution was allowed to warm to RT, stirred at RT for18 h and then poured into water and CH₂ Cl₂. The organic layer wasseparated, washed with brine, dried and concentrated in vacuo. Theresidue was purified on a silica gel column with 10% ethylacetate-hexane as eluent to give 1 g of the title compound as acolorless oil. n_(D) ²⁵ 1.5218.

Example 256

N-Ethyl-5-methyl-3-(trimethylsilyl)-2-thiophene-carboxamide.

The title compound was prepared from 5-methyl-2-thiophenecarboxylic acidusing the methods of Example 248 yielding 3.6 g as a white solid. m.p.112-115° C.

Example 257

N-Ethyl-5-iodo-3-(trimethylsilyl)-2-thiophene-carboxamide.

The compound of Example 248 was reacted with iodine using the method ofstep c of Example 248 to give 0.5 g of the title compound as a whitesolid. m.p. 85-88° C.

Example 258

N-Ethyl-5-formyl-3-(trimethylsilyl)-2-thiophene-carboxamide.

a) To diisopropylamine (12.6 g, 0.125 mol) in 100 mL THF was addedslowly 2.5M n-BuLi in hexane (52 mL, 0.13 mol) at -40° C. and stirred at-40° C. for 0.5 h. The solution was cooled to -60° C. and a solution ofthe compound of Example 248 (12.1 g) in 60 mL THF was added and stirringwas continued at between -50 and -60° C. for 1 h. After that thereaction mixture was poured into ether-dry ice slush and extracted withwater. The aq layer was acidified with conc HCl and extracted with CH₂Cl₂. The organic layer was washed with brine, dried and concentrated invacuo to afford5-[(ethylamino)-carbonyl]-4-(trimethylsilyl)-2-thiophenecarboxylic acid.

b) To a solution of the acid of step a (3.6 g, 12 mmol) in 30 mL THF wasadded dropwise 30 mL of 1M of diborane in THF at 0° C. After theaddition was complete, the resulting reaction mixture was stirred at RTfor 1 h, then cautiously poured into ice-water and extracted with CH₂Cl₂. The organic water was washed with brine, dried and concentrated invacuo. The crude product was purified by flash chromatography with 30%ethyl acetate-hexane as eluent to give 2.5 g ofN-ethyl-5-(hydroxymethyl)-3-(trimethylsilyl)-2-thiophene-carboxamide.

c) To the compound of step b (1.3 g, 5 mmol) in 40 mL CH₂ Cl₂ containing1.8 g celite was added 2.4 g pyridinium chlorochromate and the resultingreaction mixture was stirred at RT for 2 h. The CH₂ Cl₂ solution wasfiltered through celite, washed with water, brine, dried andconcentrated in vacuo. The residue was purified by flash chromatographywith 10% ethyl acetate-hexane to give 1.1 g of the desired product as alight yellow solid, m.p. 62-65° C.

Example 259

N-Ethyl-4-(trimethylsilyl)-5-isothiazolecarboxamide.

a) 5-Isothiazolecarboxylic acid was prepared from isothiazole, n-BuLiand dry ice according to the method of step a of Example 258.

b) This compound was converted to the title compound by reaction with70% aq ethylamine, followed by TMSCl, using the methods of Example 248to give 0.3 g of the title compound as a yellow oil. n_(D) ²⁵ 1.5275.

Example 260

N-Ethyl-5-(methylsulfinyl)-3-(trimethylsilyl)-2-thiophenecarboxamide.

To a solution of 3.4 g of a 50:50 mixture of the compound of example 248and 5-(methylthio)-3-(trimethylsilyl)-2-thiophenecarboxamide (obtainedfrom the reaction of compound of example 248 and methylmethanethiosulfonate using the method of step c of Example 248) in 30 mLmethanol was added sodium periodate (1 g, 4 mmol) and the resultingreaction mixture was stirred at RT for 18 h. After that, the solvent wasremoved in vacuo and the residue was chromatographed on a silica gelcolumn with 10%, 30% and then 70% ethyl acetate-hexane to give 1 g ofthe title compound as a white solid. m.p. 71-76° C.

Example 261

N-Ethyl-5-(methylthio)-3-(trimethylsilyl)-2-thiophene-carboxamide.

To a solution of the compound of Example 260 (0.6 g) and NaI (0.8 g) in10 mL acetone was added slowly 0.4 mL trifluoroacetic anhydride at 0° C.and the mixture was stirred at 0° C. for an additional hour. Then CH₂Cl₂ and aq sat sodium meta-bisulfite were added. The organic layer wasseparated, washed with brine, dried and concentrated. Flashchromatography of the residue with 10% ethyl acetate-hexane gave 0.5 gof the title compound as a white solid. m.p. 58-61° C.

Example 262

5-Chloro-N-(2-propenyl)-3-(trimethylsilyl)-2-thiophene-carboxamide.

The title compound was prepared from 5-chloro-2-thiophenecarboxylic acidand allylamine, followed by reaction with TMSCl using the methods ofExample 248 to afford 0.7 g of the title compound as a white solid. m.p.63-66° C.

Example 263

5-Chloro-N-(2-hydroxyethyl)-3-trimethylsilyl-2-thiophenecarboxamide.

According to the method of step c of Example 248, a solution of5-chloro-2-thiophenecarboxylic acid (3.3 g, 20 mmol) in THF was reactedwith 20 mL 2.5M n-BuLi in hexane and then quenched with 8 mL TMSCl togive crude 5-chloro-3-(trimethylsilyl)-2-thiophenecarboxylic acid.

This acid and a catalytic amount of DMF in 10 mL thionyl chloride wasrefluxed for 2 h, then cooled to RT and excess thionyl chloride wasremoved in vacuo. The crude acid chloride was reacted with2-aminoethanol according to the method of step b of Example 248 to give0.9 g of the title compound as a white solid, m.p. 110-114° C.

Example 264

5-Chloro-N-(2-chloroethyl)-3-(trimethylsilyl)-2-thiophenecarboxamide.

A solution of the compound of Example 263 (0.4 g) and 1 mL thionylchloride in 6 mL CH₂ Cl₂ was refluxed for 1 h, then cooled and pouredinto ice-water. Additional CH₂ Cl₂ was added. The organic layer wasseparated, washed with brine, dried and concentrated. Flashchromatography of the residue with 5% ethyl acetate-hexane as eluentgave 0.4 g of the desired product as a white solid. m.p. 68-72° C.

Example 265

5-Chloro-N-[2[(methylsulfonyl)oxy]ethyl]-3-(trimethylsilyl)-2-thiophenecarboxamide.

To a solution of the compound of Example 263 (0.4 g) and 0.5 mLtriethylamine in 10 mL CH₂ Cl₂ at 0° C. was added methanesulfonylchloride (0.2 mL) and the resulting reaction solution was stirred at RTfor 2 h. Water was added and the two layers were separated. The organicsolution was washed with brine, dried and concentrated. Purification byflash chromatography with 30% ethyl acetate-hexane gave 0.4 g of productas a white solid. m.p. 82-86° C.

Example 266

5-Bromo-N-ethyl-3-(trimethylsilyl)-2-thiophene-carboxamide.

The title compound was prepared from the compound of Example 248 andbromine according to step c of Example 248. Purification by flashchromatography with 5% ethyl acetate-hexane gave 0.6 g of the product asa white solid. m.p. 96-98° C.

Example 267

4-Bromo-N-ethyl-2-(trimethylsilyl)-3-thiophene-carboxamide.

a) To a solution of 3,4-dibromothiophene (15 g, 62 mmol) in 80 mL etherunder a positive nitrogen atmosphere was added dropwise 75 mL 1.7Mt-BuLi in pentane at below -73° C. and the resulting reaction solutionwas stirred at -78° C. for 0.5 h. After that, the ether solution waspoured into dry ice and extracted with water. The aq solution was washedwith ether and then acidified with concentrated HCl. The solid wasfiltered and air-dried to give 9 g of 4-bromo-3-thiophene-carboxylicacid, yield 70.3%.

b) N-Ethyl-4-bromo-3-thiophenecarboxamide was prepared from4-bromo-3-thiophenecarboxylic acid (7 g, 34 mmol) and 70% ethylamine inwater according to steps a and b of Example 248 in 64.5% yield.

c) A solution of this compound (1.9, 8.1 mmol) in THF was metallatedwith LDA (prepared by diisopropylamine and 2.5M of n-BuLi in hexaneusing the method of Example 250) and quenched with TMSCl according tothe method of step c of Example 248 to give 1.1 g of the title compoundas a white solid in 44.5% yield. m.p. 93-96° C.

Example 268

5-Bromo-N-ethyl-2-(trimethylsilyl)-3-thiophene-carboxamide.

a) To a solution of 3-thiophenecarboxylic acid (7.7 g, 60 mmol) in 70 mLacetic acid was added a solution of 9.6 g bromine in 50 mL acetic acidat RT and stirring was continued at RT for 0.5 h. After that, thereaction mixture was poured into 600 mL ice-water. The precipitate wasfiltered, washed with water and air-dried to give 7.9 g of5-bromo-3-thiophenecarboxylic acid.

b) 5-Bromo-N-ethyl-3-thiophenecarboxamide was prepared from5-bromo-3-thiophenecarboxylic acid (2.1 g, 10 mmol) and 70% ethylaminein water according to the methods of steps a and b of Example 248 in 70%yield.

c) The compound of step b (1.3 g, 5.6 mmol) was metallated with LDA(prepared from diisopropylamine and 2.5M n-BuLi in hexane as in Example250) and reacted with TMSCl as in step c of Example 248 to give 70.6% ofthe title compound as a white solid. m.p. 96-98° C.

Example 269

N-Ethyl-2,5-bis(trimethylsilyl)-3-thiophenecarboxamide.

To a solution of 5-bromo-3-thiophenecarboxylic acid in 40 mL THF under apositive nitrogen atmosphere was added dropwise a solution of 9 mL of2.5M n-BuLi in hexane at below -70° C. and the resulting reactionsolution was stirred at -78° C. for 1 h. Then 3.6 mL TMSCl was added atbelow -70° C. and stirring was continued for 1 h at -78° C. The solutionwas allowed to warm to 0° C. and poured into water and washed withether. The aq layer was separated, acidified with conc HCl and extractedwith CH₂ Cl₂. The organic solution was dried over MgSO₄ and concentratedto give a mixture of acids.

The acids were converted to the corresponding ethyl amides as in steps aand b of Example 248 and the mixture was purified by flashchromatography with 10% ethyl acetate-hexane to give 0.4 of the titlecompound as a white solid. m.p. 106-111° C.

Example 270

N-Ethyl-2-(trimethylsilyl)-4,5,6,7-tetrahydro-benzo[B]thiophene-3-carboxamide.

a) To a mixture of cyclohexanone (20 g, 0.2 mol), ethyl cyanoacetate(22.6 g, 0.2 mol) and sulfur (6.8 g 0.22 mol) in 70 mL absolute ethanolwas added rapidly 20 mL diethylamine. The reaction mixture wasoccasionally cooled with a water bath to maintain the temperature below60° C. and then stirred at between 30 to 46° C. for 2 h. Then water wasadded. The precipitate was filtered, air-dried and recrystallized fromethanol to give 31 g of ethyl2-amino-4,5,6,7-tetrahydrobenzo[B]-3-carboxylate.

b) To copper (II) bromide (14 g) and 90% t-butyl nitrite (10 mL) in 40mL acetonitrile at 50° C. was added in portions 11 g of the amine ofstep a, such that the temperature did not exceed 65° C. After theaddition was complete, the resulting reaction mixture was stirred for anadditional 0.5 h, then partitioned between water and ethyl acetate. Theethyl acetate solution was then washed with water, brine, dried andconcentrated. The crude product was chromatographed with 2% ethylacetate-hexane to give 6.5 g of a 3:1 mixture of ethyl2-bromo-4,5,6,7-tetrahydrobenzo[B]thiophene-3-carboxylate and ethyl4,5,6,7-tetrahydrobenzo-[B]thiophene-3-carboxylate.

A solution of the mixture of ethyl esters (5 g) and potassium hydroxide(3 g) in 20 mL ethanol was refluxed for 2 h, cooled and the solventremoved in vacuo. Water was added to the solid and the aq solution wasacidified with conc HCl. The solid was filtered, washed with water andair dried to give 3.8 g of a mixture of acids.

A mixture of the two acids (3.3 g) and a catalytic amount of DMF in 10mL thionyl chloride was refluxed for 2 h, then cooled and concentratedin vacuo. This mixture of crude acid chlorides was dissolved in 20 mLCH₂ Cl₂ and added to 20 mL 70% ethylamine in water at below -20° C. andthe mixture was stirred at RT for 18 h. The organic layer was separated,washed with water, brine, dried and concentrated. Flash chromatographyof the crude with 15% ethyl acetate-hexane gave 3.2 g of2-bromo-N-ethyl-4,5,6,7-tetrahydrobenzo[B]thiophene-3-carboxamide and0.4 g of N-ethyl-4,5,6,7-tetrahydro-benzo[B]thiophene-3-carboxamide.

c) The 2-bromo compound was reacted with TMSCl according to the methodof step c of Example 248. Purification by column chromatography with 12%ethyl acetate-hexane afforded 1.1 g of the title compound as a whitesolid. m.p. 107-112° C.

Example 271

4,5-Dimethyl-N-ethyl-2-(trimethylsilyl)-3-thiophene-carboxamide.

Using the procedures for the synthesis of the compound of Example 270and methyl ethyl ketone as the starting material, the title compound wasobtained as a hite solid. m.p. 90-94° C.

Example 272

N-Ethyl-N-(methylthio)-3-(trimethylsilyl)-2-thiophene-carboxamide.

To a solution of the compound of Example 248 (1.6 g, 6.5 mmol) in 20 mLTHF under a positive nitrogen atmosphere was added dropwise 3 mL of 2.5Mn-BuLi in hexane at below -70° C. and the resulting solution was stirredat -78° C. for 1 h. A solution of methyl methanethiosulfonate (0.9 g,7.1 mmol) in THF was then added dropwise at below -70° C. and stirringwas continued for an additional hour at -78° C. After that, the solutionwas warmed to 0° C. and poured into water. CH₂ Cl₂ was added. The aqlayer was separated and extracted with CH₂ Cl₂. The combined organiclayers were washed with brine, dried (MgSO₄) and concentrated.Purification of the crude on a silica gel column with 10% ethylacetate-hexane gave 1.2 g of the title compound as a colorless oil.n_(D) ²⁴ 1.5519.

Example 273

5-Chloro-N-(methylthio)-N-2-propenyl-3-(trimethylsilyl)-2-thiophenecarboxamide.

The compound of Example 262 (1.1 g) was reacted with 0.52 g of methylmethanethiosulfonate using procedure described for the preparation ofthe compound of Example 272. The title compound (0.6 g) was purified byflash chromatography with 2% ethyl acetate-hexane and recovered as acolorless oil. n_(D) ²⁵ 1.5698.

Example 274

N-Ethyl-3-(trimethylsilyl)-4.5,6,7-tetrahydro-benzo[B]thiophene-2-carboxamide.

To 9.4 mL DMF in 30 mL 1,2-dichloroethane was added dropwise 9.3 mLphosphorus oxychloride at below 10° C. The mixture was allowed to warmto RT and 10.3 mL cyclohexanone in 10 mL 1,2-dichloroethane was added.After the addition, the mixture was heated at 60-65° C. for 3 h, thencooled to RT and a solution of 30 g of sodium acetate in 60 mL water wasadded at below 20° C. The organic layer was separated, washed withwater, brine and dried.

To the crude aldehyde in 1,2-dichloroethane was added in 1 portion 9 mLmethyl thioacetate, followed by dropwise addition of 20 mLtriethylamine. The reaction was exothermic and the mixture was stirredat ambient temperature for 18 h. After that, the organic layer waswashed with 3N HCl, water, brine, dried and concentrated.

To this oil were added 4 mL 20% sodium methoxide in methanol and 60 mLmethanol and the resulting solution was heated at reflux for 2 h. Thesolution was cooled and the solvent was removed in vacuo. Water and CH₂Cl₂ were added. The organic layer was separated, washed with brine,dried and concentrated to give 12.6 g of crude methyl4,5,6,7-tetrahydrobenzo[B]thiophene-2-carboxylate as an oil.

A mixture of 2.2 g of this methyl ester and 20 mL of 70% ethylamine inwater was stirred at RT for 72 h. After that water and CH₂ Cl₂ wereadded. The organic layer was separated, washed with brine, dried andconcentrated to give 2 g of ethyl amide as a light yellow solid,m.p.133-135° C.

The title compound was prepared from this ethyl amide (1.1 g, 5 mmol)and TMSCl according to the method of step c of Example 248. Purificationby flash chromatography with 10% ethyl acetate-hexane gave 1 g of theproduct as a white solid. m.p. 126-128° C.

Example 275

N-Ethyl-5-(methylamino)-2-(trimethylsilyl)benzamide.

To a solution of the compound of Example 217 (0.29 g, 1.2 mmol) andbenzotriazole (0.143 g, 1.2 mmol) in absolute ethanol (5 mL) at RT wasadded 37% aq formaldehyde (0.090 mL, 1.2 mmol). An aliquot was inducedto precipitate by cooling and addition of a small amount of water. Theprecipitate was added back into the reaction which was stirred at RTovernight and cooled in a refrigerator for 6 h. The resultant mixturewas filtered and dried under vacuum (P₂ O₅) to afford5-[(1H-benzotriazol-1-ylmethyl)amino]-N-ethyl-2-(trimethylsilyl)benzamideas a white solid (0.308 g, 70%). m.p. 207-208° C.

A mixture of this compound (0.222 g, 0.6 mmol) and sodium borohydride(45 mg, 1.2 mmol) in THF (10 mL) was heated at reflux for 30 min. Thecool reaction was poured into water, made basic with 2.5 N NaOH andextracted with ether. The organic layers were washed with brine, dried(MgSO₄) and concentrated. The crude product was purified byrecrystallization from hexanes to afford the title compound as a whitesolid (0.114 g, 76%). m.p. 101-102° C.

Example 276

2-Chloro-N-ethyl-6-(trimethylsilyl)-3-[(trimethylsilyl)-ethynyl]benzamide.

To a slurry of the compound of Example 239 (0.763 g, 2.0 mmol),bis(triphenylphosphine)palladium dichloride (28 mg, 0.04 mmol) andcuprous iodide (15 mg, 0.08 mmol) in anhydrous triethylamine (10 mL) wasadded trimethylsilylacetylene (0.236 g, 2.4 mmol). The brown slurry wasstirred at RT for 3.5 h, concentrated, slurried in ether and filteredthrough silica gel (ether). The crude product was further purified byflash chromatography (ethyl acetate/hexanes) followed byrecrystallization from hexanes to afford the title compound as whitecrystals (0.618 g, 88%). m.p. 131-132° C.

Example 277

2-Chloro-3-ethenyl-N-ethyl-6-(trimethylsilyl)benzamide.

To a solution of the compound of Example 239 (0.382 g, 1.0 mmol),tetrakis(triphenylphosphine)-palladium(O) (23 mg, 0.02 mmol) and2.6-di-t-butyl-4-methylphenol (1.5 mg) in toluene (10 mL) was addedvinyltributyltin (0.349 g, 1.1 mmol). The light yellow solution washeated at reflux for 24 h, additionaltetrakis(triphenylphosphine)palladium(O) (15 mg) was added, and refluxwas continued for 24 h. The cool mixture was diluted with ether,filtered through Celite, concentrated and purified by RC (ethylacetate/hexanes). The product was further purified by recrystallizationfrom pentane to afford the title compound as white needles (0.060 g,21%). m.p. 127-128° C.

Example 278

[2-Chloro-6-(trimethylsilyl)benzoyl]ethylphosphoramidic acid, diethylester.

To a solution of 5.0 g (29.0 mmol) of diethyl chlorophosphate in 70 mLdichloroethane cooled on an ice bath was added 4.1 g (63.8 mmol) ofethylamine (70% aq). The mixture was allowed to stir at RT for 30 minand was then partitioned between ether and water. The organic layer waswashed with brine, dried (MgSO₄), and was filtered. The filtrate wasevaporated in vacuo and the residue was kugelrohr distilled (0.8 torr,90° C.) to yield 2.7 g (52%) of diethyl N-ethylphosphoramidate as acolorless oil.

To a solution of 0.8 g (4.4 mmol) of this phosphoramidate in 40 mL dryTHF cooled to -70° C. was added 1.8 mL (4.5 mmol) of n-BuLi (2.5 M inhexane). The mixture was stirred at -70° C. for 10 min and to themixture was added a solution of 1.0 g (4.05 mmol) of the compound ofExample b in 10 mL dry THF. The mixture was allowed to warm to RT andwas stirred for another 45 min. The mixture was then heated to refluxfor 30 min and was allowed to cool to RT. The mixture was partitionedbetween ether and water. The organic layer was washed with brine, dried(MgSO₄), and was filtered through silica gel. The filtrate wasevaporated in vacuo and the residue was chromatographed (HPLC, 35% ethylacetate/hexane) to yield 1.0 g (62%) of a colorless oil. n_(D) ²⁵=1.5060.

Example 279

2-Chloro-N-ethyl-N-[(methylthio)methyl]-6-(trimethylsilyl)benzamide.

To a solution of 2.0 g (7.8 mmol) of the compound of Example 45 in 30 mLdry THF was added 7.9 mL (7.9 mmol) sodium bis(trimethylsilyl)amide (1.0M in THF). To the resulting mixture was added 1.0 g (10.4 mmol)chloromethyl methylsulfide. The mixture was stirred for 15 min andanother 0.65 g (6.7 mmol) of chloromethyl methylsulfide was added.Stirring at RT was continued for 1 h and the mixture was then heated toreflux for 28 hours. The mixture was allowed to cool to RT and was thenpartitioned between ether and water. The organic layer was washed withbrine, dried (MgSO₄), and was filtered through silica gel. The filtratewas evaporated in vacuo and the residue was chromatographed (HPLC, 8%ethyl acetate/hexane) to yield 1.1 g (45%) of a colorless oil. n_(D) ²⁵=1.5526.

Example 280

2-[(1,1-Dimethylethyl)sulfonyl]-N-ethyl-6-fluoro-benzamide.

A 0° C. solution of N-ethyl 2-fluoro-6-(1,1-dimethylethylthio)benzamide,described in Example 194, (0.15 g, 0.59 mmol) in methanol (5 mL) wascombined with a 0° C. solution of OXONE® (1.08 g, 1.76 mmol) in water (5mL). This mixture was stirred overnight, then was poured into 25% aqsodium metabisulfite (100 mL) and extracted with ether (3×100 mL). Thecombined organics were washed with brine followed with water, then wasdried (MgSO₄) and concentrated to give the title compound as a clearoil.

Example 281

2-Chloro-6-[(1,1-dimethylethyl)methylamino]-N,N-(diethyl)benzamide.

A solution of the N-tert-butyl b-lactam (3.3 g, 18.9 mmol) described inExample 188 and diethylamine (4.6 g, 62.4 mmol) in CH₂ Cl₂ (100 mL) wasstirred at RT overnight. The solvent was evaporated, then the residuewas triturated with cyclohexane and the filtrate was concentrated to anoil. 500 mg of this material was purified by RC with EtOAc/cyclohexaneto give 478 mg of N,N-diethyl-2-(N-tert-butylamino)benzamide as anorange oil, a 95% yield.

A mixture of N,N-diethyl-2-(N-tert-butylamino)-benzamide (4.2 g, 17mmol), potassium carbonate (3.1 g, 22 mmol), and MeI (3.1 g, 22 mmol) inDMF (75 mL) was heated overnight at 40° C. The reaction was notcomplete, so additional MeI (3.1 g, 22 mmol) was added and the reactionheated at 40° C. for 1 d, then was partitioned between EtOAc and water.The EtOAc was dried (MgSO₄), concentrated, and purified by HPLC with 1:4ethyl acetate/cyclohexane to afford 3.22 g ofN,N-diethyl-2-(N-methyl-N-tert-butylamino)benzamide as a yellow oil, a72% yield.

A solution of 1.3M s-BuLi in cyclohexane (3.5 mL, 4.6 mmol) was addeddropwise to a dry-ice/acetone cooled solution of TMEDA (0.7 mL, 4.8mmol) in THF (10 mL), followed by the dropwise addition of a solution ofN,N-diethyl-2-(N-methyl-N-tert-butylamino)benzamide (1.0 g, 3.8 mmol) inTHF (5 mL). The reaction mixture was stirred at -78° C. for 50 min, thena solution of hexachloroethane (2.7 g, 11.4 mmol) in THF (5 mL) wasadded. This mixture was stirred for 30 min at -78° C., then was warmedto -30° C., diluted with water, and extracted with EtOAc (2X). Thecombined organic extracts were dried (MgSO₄), concentrated, and purifiedby HPLC with 3:17 EtOAc/cyclohexane to give 577 mg of the title compoundas a yellow oil, a 51% yield.

Example 282

2-Chloro-N-ethyl-5-(trimethylsilyl)-4-thiazole-carboxamide.

a) A mixture of 90% ethyl bromopyruvate (54.2 g, 0.25 mol) and thiourea(20 g, 0.263 mol) in 500 mL absolute ethanol was heated at reflux for 1h and then stirred at ambient temperature for 2 h. Ethanol was removedin vacuo and the residue was suspended in ice-water and neutralized withsolid potassium carbonate until basic. The solid was filtered, washedthoroughly with water and air-dried to give 42 g ofethyl-2-amino-4-thiazolecarboxylate.

b) To a mixture of copper (II) chloride (20 g, 0.15 mol) and 90% t-butylnitrite (24 mL, 0.18 mol) in 500 mL acetonitrile at 60° C. was added inportions ethyl 2-amino-4-thiazolecarboxylate (21 g, 0.12 mol),maintaining the temperature at between 60-65° C. After the addition, theresulting reaction mixture was heated at 80° C. for 1 h, then cooled toRT and poured into a mixture of water, CH₂ Cl₂ and 25 mL conc HCl. Theaq layer was separated and extracted with CH₂ Cl₂. The combined organiclayers were washed with water, brine, dried and concentrated to give21.5 g of ethyl 2-chloro-4-thiazolecarboxylate.

c) A mixture of NaOH (1.9 g, 47.5 mmol) andethyl-2-chloro-4-thiazolecarboxylate (7.6 g, 40 mmol) in 100 mL absoluteethanol was stirred at RT for 4 h. After that, ethanol was removed invacuo and the residue was dissolved in water. The aq layer was washedwith ether and then acidified with conc HCl. The solid was filtered andair dried to give 4 g of 2-chloro-4-thiazolecarboxylic acid.

d) 2-Chloro-4-thiazolecarboxylic acid chloride (prepared from2-chloro-4-thiazolecarboxylic acid, thionyl chloride and a catalyticamount of DMF) was reacted with 70% ethylamine in water to yield2-chloro-N-ethyl-4-thiazolecarboxamide. This compound was reacted withTMSCl using the method of step c of Example 248. Purification by flashchromatography with 3% ethyl acetate-hexane gave 2.5 g of the titlecompound as a light yellow oil in 55.6% yield. n_(D) ²⁶ 1.5313.

Example 283

2-Chloro-N-ethyl-3-(trimethylsilyl)-4-thiazole-carboxamide.

2-Chlorothiazole was prepared from 2-amino-thiazole according to step bof Example 282. Distillation yielded a clear liquid. b.p. 145-150° C.This compound was reacted with n-BuLi and dry ice using the method ofstep a of Example 258 to yield 2-chloro-5-thiazolecarboxylic acid.

This compound was reacted with 70% ethylamine, followed by TMSCl usingthe methods of Example 248 to yield 0.9 g of the title compound as whitesolid in 54.2% yield. m.p. 101-103° C.

Example 284

N-Ethyl-5-(trimethylsilyl)-1H-pyrazole-1-carboxamide.

To a solution of pyrazole (1.7 g, 25 mmol) and 4 mL triethylamine in 50mL dry THF was added ethyl isocyanate (2 g, 28 mmol) at 0° C. and theresulting reaction solution was stirred at RT for 18 h. Ethyl acetateand 2N HCl were added. The aq layer was separated and extracted withethyl acetate. The combined ethyl acetate layers were washed with brine,dried and concentrated in vacuo to give an oil. The oil was trituratedwith cold hexane to give 2.5 g of N-ethyl-1H-pyrazole-1-carboxamide as awhite solid.

A solution of this compound in THF was metallated with lithiumdiisopropylamide (prepared by diisopropyl-amine and 2.5M of n-BuLi inhexane as in step a of Example 250) and quenched with TMSCl as inExample 248 to give 0.6 g of the title compound as an orange oil. n_(D)²⁶ 1.6627.

Example 285

2-Chloro-N-ethyl-6-(1,1-dimethylethyl)benzamide.

2-tert-butyl-N-ethylbenzamide was prepared from 2-tert-butylbenzoylchloride, prepared in Example 186, and 70% ethylamine in water accordingto the method of step b of Example 248.

To a solution of 2-tert-butyl-N-ethylbenzamide (44 g, 215 mmol) andTMEDA (70 mL, 446 mmol) in 500 mL THF at -70° C. under a positivenitrogen atmosphere was added at a rapid stream 520 mL 1.3M s-BuLi incyclo-hexane, maintaining the temperature at below -60° C. After theaddition was complete, the resulting reaction solution was warmed to-30° C. and stirred at between -30° C. and -26° C. for 50 min. Thesolution was then cooled to below -70° C. and a solution ofhexachloroethane (80 g) in 250 mL THF was added at between -70 and -65°C. Stirring at below -70° C .was continued for 0.5 h. The resultingreaction solution was then poured into water. CH₂ Cl₂ and 3N HCl wereadded. The aq layer was separated and extracted with CH₂ Cl₂. Thecombined organic layers were washed with water, dried and concentratedin vacuo. The solid was triturated with hexane and then purified byflash chromatography with 15% ethyl acetate/hexane as eluent to give thedesired product as a white solid. m.p. 121-123° C.

Example 286

4,5-Dimethyl-N-ethyl-3-(trimethylsilyl)-2-thiophene-carboxamide.

The title compound was prepared from methyl ethyl ketone using themethods of Example 274 and was obtained as a white solid. m.p. 77-80° C.

Example 287

5-Chloro-N-hydroxy-N-(1-methylethyl)-3-(trimethylsilyl)-2-thiophenecarboxamide.

5-Chloro-3-(trimethylsilyl)-2-thiophenecarboxylic acid chloride wasprepared by the reaction of 1 g5-chloro-3-(trimethylsilyl)-2-thiophenecarboxylic acid (prepared as inExample 263) and 6 mL thionyl chloride, using the procedure of step a inExample 248. This product was dissolved in CH₂ Cl₂ at 0° C. and added toa mixture of N-isopropylhydroxylamine hydrochloride (0.55 g, 5 mmol) and4 g NaHCO₃ in 20 mL CH₂ Cl₂ and 20 mL water. The resulting reactionmixture was stirred at RT for additional 3 h. The organic layer wasseparated, washed with brine, dried and concentrated. The residue waspurified by flash chromatography with 8% ethyl acetate/hexane to give 80mg of the title compound. m.p. 146-150° C.

Example 288

N-Ethyl-1-methyl-5-(trimethylsilyl)-1H-pyrazole-4-carboxamide.

A solution of ethyl (ethoxymethylene)cyanoacetate (68 g, 0.4 mol) andmethylhydrazine (18.5 g, 0.4 mol) in 200 mL absolute ethanol wasrefluxed for 1.5 h, then cooled to RT and filtered. The filtrate wasconcentrated in vacuo and the residue was triturated with ether to give54 g of crude ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate in 75.4%yield.

To a solution of 90% t-butyl nitrite (50 mL, 0.37 mol) in 200 mL DMF wasadded in portions ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (39g, 0.23 mol), maintaining the temperature at around 30° C. After theaddition, the resulting mixture was warmed to 50° C. and stirred at thattemperature for 0.5 h. The mixture was poured into 100 mL conc HCl and40 mL water and extracted with CH₂ Cl₂. The organic solution was washedwith water, brine, dried and concentrated. Vacuum distillation of theresidue gave 32.4 g of ethyl 1-methyl-1H-pyrazole-4-carboxylate as aclear liquid. b.p. 65-80° C. at 0.1 torr.

A solution of ethyl 1-methyl-1H-pyrazole-4-carboxylate (20.2 g, 131mmol) and NaOH (6.3 g, 158 mmol) in 200 mL absolute ethanol was refluxedfor 2 h and stirring was continued at RT for 18 h. After that, thesolvent was removed in vacuo. The residue was dissolved in water. The aqsolution was washed with ether and acidified with concentrated HCl. Thesolid was filtered, washed with water and air-dried to give 14.2 g of1-methyl-1H-pyrazole-4-carboxylic acid in 86% yield.

N-Ethyl-1-methyl-1H-pyrazole-4-carboxamide was prepared from1-methyl-1H-pyrazole-4-carboxylic acid and 70% ethylamine in water usingthe methods of steps a and b of Example 248. The product was purified byflash chromatography with 10% ethyl acetate-hexane and recovered as awhite solid in 54.7% yield. m.p. 103-106° C.

This compound was reacted with TMSCl as in Example 248 to give 1.2 g ofthe title compound as a white solid. m.p. 77-81° C.

    ______________________________________                                        Elemental Analyses                                                              Ex No.       Elements (Calculated/Found)                                    ______________________________________                                        2          C 67.41, 66.98; H 9.29, 9.31; N 5.62, 5.52.                          3             C 68.38, 38.36; H 9.56, 9.59; N 5.62, 5.31.                     4             C 62.88, 62.95; H 8.29, 8.31; N 5.24, 5.21.                     6             C 77.68, 76.22; H 10.19, 10.18; N 5.66,                                       5.50.                                                           7             C 44.90, 44.91; H 5.92, 5.93.                                   10            C 66.82, 66.65; H 9.35, 9.37; N 4.33, 4.24.                     14            C 70.04, 69.94; H 10.03, 10.04; N 4.80,                                       4.75.                                                           15            C 59.23, 59.42; H 7.81, 7.97; N 4.93, 4.78.                     18            C 60.48, 60.37; H 8.12, 8.12; N 4.70, 4.76.                     22            C 57.86, 58.00; H 7.47, 7.52; N 5.19, 5.26.                     23            C 60.48, 60.34; H 8.12, 8.08; N 4.70, 4.75.                     35            C 65.97, 65.74; H 6.99, 6.94; N 4.05, 3.99.                     36            C 61.61, 61.93; H 8.40, 8.17; N 4.49, 4.23.                     38            C 55.70, 55.90; H 7.01, 7.07; N 4.64, 4.68.                     39            C 59.23, 59.36; H 7.81, 7.85.                                   41            C 60.98, 60.88; H 7.51, 7.52; N 4.74, 4.73.                     43            C 61.16, 61.13; H 7.98, 7.99; N 3.96, 3.94.                     44            C 69.26, 69.22; H 9.81, 9.82; N 5.05, 5.03.                     46            C 56.07, 55.96; H 7.39, 7.44.                                   50            C 63.35, 63.41; H 8.73, 8.77.                                   55            C 60.17, 59.91; H 7.74, 7.80; N 4.68, 4.63.                     56            C 58.91, 58.62; H 7.42, 7.35; N 4.91, 4.94.                     57            C 64.01, 63.88; H 8.60, 8.65; N 4.98, 4.94.                     58            C 68.38, 68.20; H 9.56, 9.62; N 5.32, 5.27.                     59            C 60.48, 60.56; H 8.12, 8.14; N 4.70, 4.68.                     60            C 69.26, 69.31; H 9.81, 9.83; N 5.05, 5.06.                     61            C 56.76, 56.79; H 6.99, 7.02; N 4.41, 4.43.                     63            C 68.38, 68.25; H 9.56, 9.47; N 5.32, 5.58.                     64            C 68.38, 68.14; H 9.56, 9.46; N 5.32, 5.61.                     66            C 62.64, 62.49; H 8.66, 8.56; N 4.30, 4.57.                     67            C 65.97, 66.01; H 6.99, 7.00; N 4.05, 4.11.                     68            C 65.27, 65.30; H 9.31, 9.17; N 3.81, 3.90.                     69            C 52.82, 52.97; H 6.65, 6.61; N 4.40, 4.44.                     77            C 52.82, 52.88; H 6.28, 6.27.                                   78            C 54.42, 54.48; H 6.68, 6.63.                                   79            C 54.42, 54.35; H 6.68, 6.63.                                   80            C 55.88, 55.99; H 7.03, 7.05.                                   81            C 55.88, 55.70; H 7.03, 6.99.                                   85            C 61.61, 61.63; H 8.40, 8.37; N 4.49, 4.47.                     88            C 55.70, 55.80; H 7.01, 7.02; N 4.64, 4.69.                     95            C 61.61, 61.50; H 8.40, 8.41; N 4.49, 4.75.                     96            C 65.27, 64.62; H 9.31, 9.16.                                   97            C 60.17, 60.42; H 7.74, 7.80.                                   98            C 64.01, 63.76; H 8.60, 8.52.                                   101           C 68.10, 68.21; H 7.79, 7.81; N 3.61, 3.66.                     104           C 67.08, 66.83; H 8.04, 7.99.                                   105           C 67.11, 67.00; H 6.76, 6.78;                                   125           C 60.79, 60.95; H 6.60, 6.56.                                   127           C 64.47, 64.58; H 9.02, 9.06.                                   128           C 58.60, 58.31; H 7.99, 7.94.                                   130           C 58.96, 59.11; H 7.42, 7.40; N 4.30, 4.25.                     164           C 59.23, 59.35; H 7.81, 7.78.                                   166           C 60.48, 60.59; H 8.12, 8.13; N 4.70, 4.71.                     169           C 56.06, 56.26; H 7.39, 7.33.                                   172           C 51.72, 51.98; H 6.68, 6.75.                                   186           C 74.71, 73.93; H 10.23, 10.08.                                 189           C 63.70, 63.78; H 8.20, 8.15; N 9.91, 9.86.                     195           C 60.17, 57.51; H 7.41, 6.65.                                   249           C 52.12, 51.45; H 8.41, 8.32; N 4.68, 4.62.                     281           C 64.74, 64.65; H 8.49, 8.48; N 9,44, 9.47.                   ______________________________________                                    

BIOLOGICAL ASSAYS

The compounds prepared in the above examples have demonstrated controlof Gg in one or both of the following test methods. The results areshown in the table below.

In vitro Assay

The test compounds (0.25 mL of an appropriate stock solution in acetone)are incorporated into 25 mL minimal media agar [prepared by autoclavinga solution of 17.5 g Czapek Dox broth (Difco), 7.5 g purified agar orBacto-agar (Difco), and 500 mL distilled/deionized water, and thenadding 50 μL of 1 mg/mL thiamine hydrochloride and 50 μL of 1 mg/mLbiotin in 5% ethanol] and plates are prepared.

Each plate is inoculated by placing in a triangular shape three 4-mmplugs of Gaeumannomyces graminis var. tritici (Ggt) grown on the minimalmedia agar described above. The plates are incubated in the dark at19-20° C. for 4 to 5 days. The growth of the fungus is measured as thediameter of the mycelial growth. The result is expressed as PercentInhibition, calculated as [1--[(mm growth on treated plate--4)/(mmgrowth on control plate--4)]]×100.

In vivo Assay

Compounds are tested for control of Ggt on `Bergen` or `Anza` varietiesof wheat grown in 3-inch square pots containing soil infested with Ggt.The infestation is accomplished by mixing the soil with an inoculumprepared by growing Ggt on 1/4 strength potato dextrose agar (4.875 gpotato dextrose agar, 5.0 g Bacto agar, 500 mL distilled, deionizedwater) in plates and using plugs from the plates to infest sterile oats(400 cc whole oats, 350 mL deionized water, autoclaved). After aone-month incubation period at room temperature, the oats are dried andmixed with the soil at 4% v/v. Four wheat seeds are placed on top of thesoil in each pot. The test compounds are prepared as an 1:9acetone/water v/v solution containing 0.18% Tween® 20 to provide atreatment rate of 0.5 mg active ingredient per pot, treated with 3 mLtest solution per pot. Five pots are used for each treatment level andthe controls, which are untreated, inoculated and non-inoculated pots.After one hour drying time, the seeds are covered with more of theappropriate soil and a layer of vermiculite. The pots are placed in agrowth chamber and watered each day. After four weeks, each pot isevaluated for evidence of disease by examination of the seminal roots ofeach plant under a dissecting microscope. A 0 to 5 rating scale havingthe following meanings is used:

0=no runner hyphae or lesions present

1=runner hyphae and a few small lesions present on <10% of root system

2=runner hyphae and small lesions present on 10-25% of root system

3=runner hyphae and lesions present on 25-50% of root system

4=runner hyphae and many, large, coalescing lesions on >50% of rootsystem

5=root system and culm completely inundated with lesions and runnerhyphae

From each set of five replicates a high and low score is eliminated anda replicate mean is calculated by the average of the remaining threescores. This mean score is then compared to the untreated control scoreand a percent disease control is calculated. These results are reportedin the Table below. If the calculation resulted in "0" or less, ascompared to the untreated control, a "N" is shown to indicate nocontrol.

    ______________________________________                                                                                     Test Results                                                      In vitro (ppm)                                    Ex. No.                                                                            10     1          0.1  In vivo                                      ______________________________________                                                  74     53         6    91                                             2                72        36        14               74                      3                75        58        19              100                      4                57     N        N              54                            5                29          N         N              24                      6                47     2      7              37                              7                 100         77        42               93                   8              100         97        19               85                      9                71         N         3                                       10                 50          N        N                                     11                 24          N         N                                    12               100      83    29               95                           13                 64        17          7              13                    14               79         40          7              92                     15                 44    N   N                                                16                76   27    11                3                              17                64        64        59               N                      18               100    N   N              97                                 19                 29   7         N              38                           20                 61        14         7              36                     21               100        100        100             100                    22                 46         N       13               91                     23                 71          N        N                                     24               100           N         N                                    25                 89       15       19               56                      26                 97        95        95               99                    27                 64        13        15               33                    28               100        100        60               86                    29               100        100        100              97                    30                 80        60         N                                     31                 96          4         N                                    32               100        100       75               85                     33               100         44         N              12                     34               100        100       97              100                     35                 93          7         3              46                    36               100         69        26               88                    37                87         63        17              83                     38              100          79        53              95                     39                92         82        49              99                     40                53     N     N                                              41                52     21    24                                             42                30     N    N                                               43                63          N         N                                     44                39          N         N                                     45              100     100     100              97                           46                44         11        15                                     47                70     N    N                                               48              100        100   74              97                           49              100         100       100              97                     50                20         10         3                                     51              100          19        N              77                      52                98         81       53              96                      53                95         19         9              65                     54                43          2        N              52                      55              100         81       49              100                      56                74        31         10              91                     57                90   N        10                                            58                55      6       13                                          59                26        N          6                                      60                19      N    N                                              61                49   29   9               1                                 62                69         3         8               9                      63                69        40    N                                           64                31        14   20                                           65              100         56        39               95                     66                58   N    N               3                                 67              100   19         N        N                                   68                41  N   8               N                                   69              100   81        51     67                                     70                44        15    N                                           71                N          8   14               50                          72                69        59    N                                           73               83        60    13                                           74               93        31          7              47                      75               31        26          5                                      76               79        45    N                                            77              100        47    13           N                               78               62        12         12                                      79               65        12         12                                      80               46          4    N                                           81               46     N         N                                           82               57          N   30             58                            83              100  100       100              99                            84              100        66     N                                           85               59          7    7                                           86               72        24    N                                            87              100        100  93              96                            88               73   N   N                                                   89              100   85    19              96                                90               89        34          6                                      93               26    N        N                                             94               86   63         9                                            95              100        62  N              63                              96               48        15    7                                            97              100        70          7                                      98              100        81         22              97                      99               95        72          5              59                      101                62        21         10                                    102                28        52         28                                    103                92        55  N              26                            104                71        26      N                                        105                84        37    3                                          106                97        95         95             100                    107                24   N    N                                                108                97    86        90                                         109                83        10         10                                    110                45        17          7                                    111               100        66         14              48                    112               100        96          81                                   113                96        26     N                                         114               100        85     38                                        115                97        97          97                                   116                33   N      N                                              117                97    94         36                                        118                38   N   N                                                 119               100     88  40                                              120               100        26    N                                          121                31          8  4                                           122                67  N  N                                                   123                89   78 11                                                 124               *62  N  N                                                   125                89          N         N                                    126                93  4  15                                                  127                74     21    N                                             128                50      8    4                                             129                26     35        9                                         130                39     13       16               1                         131                  3    6    N                                              132                46    15    54          N                                  133                18     3        13               N                         134                39     3    N               N                              135                39        17   22                                          136               100        26          3                                    137               100        61         17                                    138                97        36         14                                    139               100        53         11                                    140                81        19         19                                    141               100        64         19                                    142                59   N   N                                                 143                74   13    5                                               144                59      11     N                                           145               27      N         N                                         146               84    65  14                                                147                58    N    N                                               148               53           N         N                                    149               80           N         N                                    150               83 74  34   96                                              151               57     71   N              97                               152               86     71       N              54                           153               91     88       N              29                           154               69  N   N                                                   155               90  64      N              93                               156               72      33      9                                           157               91      23      7               0                           158               44      33          2                                       159              100      55        12                0                       160               88      63        17                5                       161               61      17        22                                        162               57   N         3                                            163              100    85        24                                          164               70       3         3                                        165              100    76     N              63                              166               73   N   4              15                                  167               96   86        46               93                          168              100       96        57                                       169              100       31    N                                            170               63        9  12                                             171               97       88        48               87                      172              100      100       94               99                       173               92      12          4                                       174              100      65        12                0                       175               60      48        35                                        176               97      97        83                                        177              100      19        11                                        178               54      15     N                                            179               91     88   85               97                             180               90      82        85               96                       181               58      33        12                                        182               73      58        30                                        183               56      35        24                                        184                83     11   N                                              185                72     56   48                                             186                67   N   N                                                 187                97  27   13              24                                188              100         71         29              15                    189                65        13          4                                    190                80        76         24                                    191                88        88         60              88                    192                95        95         86              99                    193                57        30         35                                    194              100        100         82                                    195                56        29         35                                    196              100         56          3                                    197                85        23          3                                    198                75        32          7                                    199                74        29          9                                    200              100        100         92              65                    201              100         50         31              65                    202                88        58         33               3                    203                91        84         79                                    204                74    N  N              43                                 205                81  47   5                                                 206              100         97         86                                    207                97        90         31                                    208                97        83 N                                             209              100         90    28                                         210                94        88         85              74                    211                90        82  N              96                            212                90        54   77              96                          213                79        82          9              87                    214                77          6         3                                    215              100         96         46              57                    216                92        54         25              68                    217              100         68         16               0                    218              100         94         18              99                    219              100         94         50              97                    220               100       100         75              97                    221                85         46        15                                    222                96  N  N                                                   223                96 93  48              82                                  224                93     27  N              21                               225                95    64    18                                             226               100         91        32                                    227               100         68        36              34                    228                96         87   N              84                          229                88         28         N                                    230                96         96   88                                         231                96         76    N                                         232                95         97    92              78                        233                76         24        28                                    234                81         32     N                                        235                70      N    3                                             236                86     68     N                                            237                96         93    44                                        238                72    N    N                                               239                87   57  22                                                240                65         22        26                                    241               100         87        13                                    242                67    N        27                                          243                83    10        23                                         244                53         20        10                                    245               100       100         50                                    246                61    2       N                                            247                59    16         N                                         248               100    10  10                                               249               100    48        17              60                         250                41  N        N                                             251                97 36        3                                             252               100   28    5                                               253                62         14   N                                          254               100    97       97              40                          255                73   N   N                                                 256               100         N          N                                    257               100  23  3                                                  258                42        19         19                                    259               *80        11         19                                    260                77   N  N                                                  261                78 25   14                                                 262               100        70         13                                    263                50  N          7                                           264               100  88          2                                          265               100        14          5                                    266               100        61         21               4                    267                61        64         18                                    268               100  N    N                                                 269               100  91          N               4                          270               100     100    96              87                           271               100       100         95              97                    272               100        23         14               0                    273               100        48         35                                    274                67        10    N                                          275                94        81     22                                        276                84        63    N                                          277                94        81    69                                         278                75        50   N                                           279                47  N  N                                                   280                38 21   24                                                 281                43  N          4                                           282                78  15          3                                          283                42    3   N                                                284               *91    35  23                                               285                75   50  N                                                 286               100    93    76                                             287                78        71         64                                    288                53   N  N                                                ______________________________________                                         *Tested at 50 ppm.                                                       

Field Tests

The compounds of Examples 1-90, 93-99, and 101-288 are combined withvarious adjuvants, carriers, and other additives and mixed with wheatand barley seed at rates of from 0.01 to 50 g active ingredient per kgof seed which reduce the incidence of Gg in previously infested fieldscompared to check fields seeded with untreated seed.

COMPOSITION EXAMPLES

    ______________________________________                                                              Wt. Pct.                                                ______________________________________                                        Suspension Concentrate:                                                         Compound No. 45                              48.900                           Polyoxypropylene-polyoxyethylene block    2.500                               copolymer                                                                     Sodium Lignin Sulfonate                      2.040                            10% Dimethylpolysiloxane Emulsion            1.020                            1% Xanthan gum solution                      0.990                            Water                                        43.250                           Emulsifiable Concentrate:                                                     Compound No. 26                              13.5                             Ethoxylated sorbitan (20EO)                   5.0                             C9 Aromatics                                81.5                              Wettable Powder:                                                              Compound No. 12                              75.0                             Sodium lignin sulfonate                       3.0                             Sodium N-methyl-N-oleyl-taurate               1.0                             Kaolinite clay                               11.0                             Granule:                                                                      Compound No. 138                              1.0                             Propylene glycol                              5.0                             Montmorillonite (24/48 mesh)                 94.0                             Dust:                                                                         Compound No. 48                            50.0                               Graphite                                   10.0                               Kaolinite clay                             40.0                             ______________________________________                                    

From the foregoing, it will be seen that this invention is one welladapted to attain all the ends and objects hereinabove set forthtogether with advantages which are obvious and which are inherent to theinvention.

It will be understood that certain features and subcombinations are ofutility and may be employed without reference to other features andsubcombinations. This is contemplated by and is within the scope of theclaims.

Since many possible embodiments may be made of the invention withoutdeparting from the scope thereof, it is to be understood that all matterherein set forth or shown in the accompanying drawings is to beinterpreted as illustrative and not in a limiting sense.

What is claimed is:
 1. A method of controlling disease in a plant causedby Gaeumannomyces sp. comprising applying to the plant locus acomposition comprising a fungicidally effective amount of a fungicide ofthe formula ##STR3## wherein Z₁ and Z₂ are C and are part of an aromaticring which is furan; andA is selected from the group consisting of--C(X)--amine wherein the amine is substituted with a first and a secondamine substituent or with an alkylaminocarbonyl and a hydrogen,--C(O)--SR₃, --NH--C(X)R₄, and --C(═NR₃)--XR₇ ; the first aminesubstituent is selected from the group consisting of C₁ -C₁₀ straight orbranched alkyl, alkenyl, or alkynyl groups or mixtures thereof,optionally substituted with one or more halogen, hydroxy, alkoxy,alkylthio, nitrile, alkylsulfonate, haloalkylsulfonate, phenyl, a5-membered heteroaryl, C₃ -C₆ cycloalkyl and C₅ -C₆ cycloalkenyl; phenyloptionally substituted with one or more C₁ -C₄ straight or branchedalkyl, alkenyl, or alkynyl groups or mixtures thereof, cycloalkyl,cycloalkenyl, haloalkyl, alkoxy and nitro; C₃ -C₆ cycloalkyl, C₅ -C₆cycloalkenyl, alkoxy, alkenoxy, alkynoxy, dialkylamino, and alkylthio;and the second amine substituent is selected from the group consistingof hydrogen, C₁ -C₆ straight or branched alkyl, alkenyl, or alkynylgroups or mixtures thereof optionally substituted with one or morehalogen; hydroxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, anddialkylphosphonyl; B is --W_(m) --Q(R₂)₃ or selected from o-tolyl,1-naphthyl, 2-naphthyl, and 9-phenanthryl, each optionally substitutedwith halogen or R₄ ; Q is C, Si, Ge, or Sn; W is --C(R₃)_(p) H.sub.(2-p)--; or when Q is C, W may also be selected from --N(R₃)_(m) H.sub.(1-m)--, --S(O)_(p--), and --O--; X is O or S; n is 2; m is 0 or 1; p is 0,1, or 2; wherein the two R groups are combined to form a ionheterocyclicring fused to said furan ring which is not benzofuran when A is C(X)amine, B is W_(m) (Q)(R₂)₃, and Q is C or Si, said R groups beingselected from the group consisting of C₁ -C₄ alkyl, alkenyl, C₃ -C₆cycloalkyl and cycloalkenyl, each optionally substituted with hydroxy,thio, phenyl, C₁ -C₄ alkoxy, alkylthio, alkylsulfinyl, or alkylsulfonyl;and each R₂ is independently selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl and phenyl, each optionally substituted with R₄or halogen; and wherein, when Q is C, R₂ may also be selected fromalkoxy, alkylthio, alkylamino, and dialkylamino; wherein further when Qis C, then two R₂ groups may be combined to form a cycloalkyl group withQ; R₃ is C₁ -C₄ alkyl; R₄ is C₁ -C₄ alkyl, haloalkyl, alkoxy, alkylthio,alkylamino, or dialkylamino; and R₇ is C₁ -C₄ alkyl, haloalkyl, orphenyl, optionally substituted with halo, nitro, or R₄ ; provided that Bis not trimethylsilyl when A is (diethylamino)carbonyl; or an agronomicsalt thereof.
 2. The method of claim 1 wherein A is --C(O)--amine,wherein the first amine substituent is C₁ -C₁₀ straight or branchedalkyl, alkenyl or alkynvl group, optionally substituted with one or morehalogen, and the second amine substituent is hydrogen.
 3. The method ofclaim 2 wherein in --W_(m) --, m is
 0. 4. The method of claim 3 whereinQ is Si.
 5. The method of claim 4 wherein each R₂ is independentlyselected from alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, andphenyl.
 6. The method of claim 5 wherein each R₂ is C1-C4 alkyl orhaloalkyl.
 7. The method of claim 6 wherein each R₂ is methyl.
 8. Themethod of claim 7 wherein A is alkylaminocarbonyl ordialkylaminocarbonyl.
 9. The method of claim 8 wherein A isethylaminocarbonyl.
 10. The method of claim 2 wherein W_(m) is --O-- andQ is C.
 11. The method of claim 10 wherein R₂ is C1-C4 alkyl orhaloalkyl.
 12. The method of claim 11 wherein A is alkylaminocarbonyl ordialkylaminocarbonyl.
 13. The method of claim 12 wherein A isethylaminocarbonyl.
 14. The method of claim 2 wherein W_(m) is --NH-- or--N(CH₃)-- and Q is C.
 15. The method of claim 14 wherein R₂ is C1-C4alkyl or haloalkyl.
 16. The method of claim 15 wherein A isalkylaminocarbonyl or dialkylaminocarbonyl.
 17. The method of claim 16wherein A is ethylaminocarbonyl.
 18. The method of claim 2 wherein B is1-naphthyl or 2-naphthyl.
 19. The method of claim 2 wherein B is9-phenanthryl.
 20. The method of claim 2 wherein B is o-tolyl.
 21. Themethod of claim 20 wherein B is o-tolyl substituted with halogen or R₄.22. The method of claim 20 wherein A is alkylaminocarbonyl ordialkylaminocarbonyl.
 23. The method of claim 22 wherein A isethylaminocarbonyl.
 24. The method of claim 2 wherein in W_(m), m is 0and Q is C.
 25. The method of claim 24 wherein R₂ is C1-C4 alkyl orhaloalkyl.
 26. The method of claim 25 wherein each R₂ is methyl.
 27. Themethod of claim 26 wherein A is alkylaminocarbonyl ordialkylaminocarbonyl.
 28. The method of claim 27 wherein A isethylaminocarbonyl.
 29. The method of claim 1 wherein the compositionalso comprises an adjuvant and wherein the fungicidally effective amountof the fungicide is an amount which is effective to control Take-all.30. A compound of the formula ##STR4## wherein Z₁ and Z₂ are carbons ofa furan ring; A is selected from the group consisting of --C(X)--aminewherein the amine is substituted with a first and a second aminesubstituent or with an alkylaminocarbonyl and a hydrogen, --C(O)--SR₃,--NH--C(X)R₄, and --C(═NR₃)--XR₇ ;the first amine substituent which isselected from the group consisting of C₁ -C₁₀ straight or branchedalkyl, alkenyl, or alkynyl groups or mixtures thereof optionallysubstituted with one or more halogen, hydroxy, alkoxy, alkylthio,nitrile, alkylsulfonate, haloalkylsulfonate, phenyl, a 5-memberedheteroaryl, C₃ -C₆ cycloalkyl and C₅ -C₆ cycloalkenyl; phenyl optionallysubstituted with one or more C₁ -C₄ straight or branched alkyl, alkenyl,or alkynyl groups or mixtures thereof, cycloalkyl, cycloalkenyl,haloalkyl, alkoxy and nitro; C₃ -C₆ cycloalkyl, C₅ -C₆ cycloalkenyl,alkoxy, alkenoxy, alkynoxy, dialkylamino, and alkylthio; and the secondamine substituent which is selected from the group consisting ofhydrogen, C₁ -C₆ straight or branched alkyl, alkenyl, or alkynyl groupsor mixtures thereof optionally substituted with one or more halogen;hydroxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, anddialkylphosphonyl; B is --W_(m) --Q(R₂)₃ or selected from o-tolyl,1-naphthyl, 2-naphthyl, and 9-phenanthryl, each optionally substitutedwith halogen or R₄ ; Q is C, Si, Ge, or Sn; W is --C(R₃)_(p) H.sub.(2-p)--; or when Q is C, W may also be selected from --N(R₃)_(m) H.sub.(1-m)--, --S(O)p--, and --O--; X is O or S; n is 2; m is 0 or 1; p is 0, 1,or 2; wherein the two R groups are combined to form a ionheterocyclicring fused to said furan ring which is not benzofuran when A is C(X)amine, B is W_(m) (Q)(R₂)₃, and Q is C or Si, said R groups beingselected from the group consisting of C₁ -C₄ alkyl, alkenyl, C₃ -C₆cycloalkyl and cycloalkenyl, each optionally substituted with hydroxy,thio, phenyl, C₁ -C₄ alkoxy, alkylthio, alkylsulfinyl, or alkylsulfonyl;and each R₂ is independently selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl and phenyl, each optionally substituted with R₄or halogen; and wherein, when Q is C, R₂ may also be selected fromalkoxy, alkylthio, alkylamino, and dialkylamino; wherein further when Qis C two R₂ groups may be combined to form a cycloalkyl group with Q; R₃is C₁ -C₄ alkyl; R₄ is C₁ -C₄ alkyl, haloalkyl, alkoxy, alkylthio,alkylamino, or dialkylamino; and R₇ is C₁ -C₄ alkyl, haloalkyl, orphenyl, optionally substituted with halo, nitro, or R₄ ; or an agronomicsalt thereof; provided that B is not trimethylsilyl when A is(diethylamino)carbonyl.
 31. The compound of claim 30 wherein A is--C(O)--amine, wherein the first anine substituent is C₁ -C₁₀ straightor branched alkyl, alkenyl or alkynyl group, optionally substituted withone or more halogen, and the second amine substituent is hydrogen. 32.The compound of claim 31 wherein in --W_(m) --, m is
 0. 33. The compoundof claim 32 wherein Q is Si.
 34. The compound of claim 33 wherein eachR₂ is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl,haloalkyl, and phenyl.
 35. The compound of claim 34 wherein each R₂ isC1-C4 alkyl or haloalkyl.
 36. The compound of claim 35 wherein each R₂is methyl.
 37. The compound of claim 36 wherein A is alkylaminocarbonylor dialkylaminocarbonyl.
 38. The compound of claim 37 wherein A isethylaminocarbonyl.
 39. The compound of claim 31 wherein W_(m) is --O--and Q is C.
 40. The compound of claim 39 wherein R₂ is C1-C4 alkyl orhaloalkyl.
 41. The compound of claim 40 wherein R₂ is methyl.
 42. Thecompound of claim 41 wherein A is alkylaminocarbonyl ordialkylaminocarbonyl.
 43. The compound of claim 42 wherein A isethylaminocarbonyl.
 44. The compound of claim 31 wherein W_(m) is --NH--or --N(CH₃)-- and Q is C.
 45. The compound of claim 44 wherein R₂ isC1--C4 alkyl or haloalkyl.
 46. The compound of claim 45 wherein A isalkylaminocarbonyl or dialkylaminocarbonyl.
 47. The compound of claim 46wherein A is ethylaminocarbonyl.
 48. The compound of claim 31 wherein Bis 1-naphthyl or 2-naphthyl.
 49. The compound of claim 31 wherein B is9-phenanthryl.
 50. The compound of claim 31 wherein B is o-tolyl. 51.The compound of claim 50 wherein B is o-tolyl substituted with halogenor R₄.
 52. The compound of claim 50 wherein A is alkylaminocarbonyl ordialkylaminocarbonyl.
 53. The compound of claim 52 wherein A isethylaminocarbonyl.
 54. The compound of claim 31 wherein in W_(m), m is0 and Q is C.
 55. The compound of claim 54 wherein R₂ is C1-C4 alkyl orhaloalkyl.
 56. The compound of claim 55 wherein each R₂ is methyl. 57.The compound of claim 56 wherein A is alkylaminocarbonyl ordialkylaminocarbonyl.
 58. The compound of claim 57 wherein A isethylaminocarbonyl.
 59. The compound of claim 31 wherein the first aminesubstituent is selected from the group consisting of ethyl, propyl,allyl, propargyl, isopropyl, and 2-haloethyl.
 60. The compound of claim30 wherein W is --C(R₃)_(p) H.sub.(2-p) -- and p is 2.